Topical regional neuro-affective therapy with caryophyllene

ABSTRACT

A method of treating a disease state or condition in humans via topical brainstem afferent stimulation therapy via the administration of caryophyllene to the back of the neck of a human patient to provide regional neuro-affective therapy is disclosed. In certain embodiments, the drugs are incorporated into a pharmaceutically acceptable topical carrier, e.g., a cream, gel, lotion or foam.

FIELD OF THE INVENTION

The invention relates to topical regional neuro-affective therapy (“TRNATHERAPY”) with a caryophyllene(s). This is accomplished viaadministration of effective amounts of these agents on the back of theneck.

BACKGROUND OF THE INVENTION

The approximate 2½ pound human brain is comprised of the most complexmaterial known to man. The neuron, the primary functional cell of thenervous system, operates on the basis of electrical impulses that resultin the release of neurochemical substances (neurotransmitters) atspecific receptors: dopamine, serotonin, acetylcholine, norepinephrine,gamma-amino butyric acid (GABA), and many others. There are estimated tobe 80-100 billion (10 times the world population) neurons in the averagehuman brain. These neurons, in turn, make 200-300 billion codedconnections with other neurons to accomplish the complex tasks of thehuman body.

The brainstem serves as the vital pathway for relay and processing ofneural impulses flowing continuously between the brain and the rest ofthe body. It is about the size of the thumb and contains the most denseand complicated wiring systems in the human body. In addition to theaxons and dendrites (wires) that carry nerve impulses, the brainstemalso contains critical nuclei that function as electrical generators andrelays. Some of the nuclei are related to cranial nerve function whileothers serve as generators and impulse centers for pain perception, theautonomic system “fight or flight” response, wakefulness and alertness,as well as cardio-respiratory and related autonomic functions.

The endocannabinoid system (ECS) is involved in regulating a variety ofphysiological processes including appetite, pain and pleasure sensation,immune system, mood, and memory. Endocannabinoid receptors in the braininteract with cannabinoids from different sources, including(endocannabinoids (brain derived, e.g., from foods (Omega-3s andOmega-6s); phytocannabinoids (plant derived, e.g., from buds, tinctures,extracts, including tetrahydrocannabinol (THC), cannabidiol (CBD),cannabinol (CBN), etc.); and synthetic cannabinoids (such astetrahydrocannabinol (THC)). Cannabinoids are a diverse class ofchemical compounds that act on cannabinoid receptors on cells andinfluence neurotransmitter release in brain. These receptor proteinsinclude endocannabinoids produced naturally in humans and animals,phytocannabinoids in cannabis and some other plants, and chemicallymanufactured synthetic cannabinoids. PhytocannabinoidΔ9-tetrahydrocannabinol (THC) is the primary psychoactive compound ofcannabis. Cannabidiol (CBD) is another major constituent of the plant,and comprises up to 40% extracts of plant resin. At least 85 differentcannabinoids isolated from cannabis exhibit varied effects.

The medical value of cannabis or marijuana has been recognized forthousands of years. In the United States, 1800's to 1930's, medicalcannabis was widely marketed and used, promoted by traditional drugcompanies. In 1890, Parke-Davis and Eli-Lilly joint-ventured to breedCannabis Americana in Greenfield, Ind. Despite benefit in treatingdiverse conditions, potential of cannabis for psychoactive effectscreated much mis-information and labeling as “gateway drug.” There is noclass of compound with more controversy and stigma than cannabis. In1937, US Congress enacted cannabis prohibition, soon after alcoholprohibition was lifted.

There is no greater example of a “double-edged sword” in medicaltherapeutics than medical marijuana. While benefits for treatingsymptoms of diverse neurologic and psychiatric conditions have beenknown and practiced by ancient civilizations for thousands of years,marijuana's psychoactive effects have also led to abuse and labeling asa “gateway drug” for more addictive compounds. There is no class oftherapeutic compounds with more controversy and stigma thancannabinoids, active components of the cannabis plant.

The U.S. Government has indicated there is no medical benefit formarijuana and classified it Controlled Substance Category 1, as heroin.It is considered by federal law, illegal to possess or use cannabis andits associated products. However, increasing number of states havechallenged this position and legalized cannabis within their territorieswith varying restrictions and conditions for use. Even then, withinindividual states, such as in Colorado, marijuana laws vary greatly fromcounty to county.

Although defined under U.S. federal law as having no medical use, U.S.Pat. No. 6,630,507 is held by the United States Department of Health andHuman Services, covering use of cannabinoids for treating a wide rangeof diseases. It is directed to a method of treating diseases caused byoxidative stress comprising administering a therapeutically effectiveamount of a cannabinoid (e.g., cannabidiol) that has substantially nobinding to the NMDA receptor to a subject who has a disease caused byoxidative stress.

Previously, the assignee has filed for patent protection for itsinventions related to topical regional neuro-affective therapy (“TRNATHERAPY”) with cannabinoids, such as cannabidiol (CBD). This isaccomplished via administration of effective amounts of these agents onthe back of the neck. That technology is covered, e.g., by U.S. patentapplication Ser. No. 15/058,946, filed Mar. 2, 2016 (entitled “TopicalRegional Neuro-Affective Therapy with Cannabinoids”) and U.S. patentapplication Ser. No. 15/228,690 filed Aug. 4, 2016 (entitled “TopicalRegional Neuro-Affective Therapy with Cannabinoid CombinationProducts”), by of which are hereby encompassed by reference.

Caryophyllene acts on same cannabinoid receptors as “medical marijuana”and CBD, medical component of cannabis. Unlike cannabis or marijuana,caryophyllene is unregulated and completely legal in all states.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a topical formulation whichincludes one or more agents which act on same cannabinoid receptors as“medical marijuana” and CBD (the medical component of cannabis), butwhich (unlike cannabis or marijuana) is unregulated and completely legalin the United States.

It is an object of the present invention to provide a method oftreatment in humans with topical afferent neural activation therapy viathe regional administration of one or more caryophyllene(s) useful forthe treatment of such diseases or conditions that may be treated viasuch therapy.

It is an object of the present invention to provide a method for thetreatment of seizures; encephalopathy, including lethargy,focus/attentional problems, and cognitive issues: spasticity; weakness;pain, including radiculopathy and neuropathy; numbness; anxiety andother mood disorders; hypertension; Parkinson's disease; insomnia; aswell as any other disease or condition that may be treated with acannabinoid.

It is an object of the present invention to provide a method for thetreatment of seizures; epilepsy; encephalopathy, including lethargy,focus/attentional problems, and cognitive issues; spasticity; weakness(e.g., muscle weakness); pain, including radiculopathy and neuropathy,lower back pain, and fibromyalgia; numbness and/or tingling; anxiety andother mood disorders; hypertension and autonomic dysfunction;Parkinson's disease and tremors; insomnia; Bell's palsy and facial nervedysfunction; glaucoma, AIDS; cancer; PTSD; trigeminal neuralgia;hemi-facial spasms; Autism/Asperger's; attention Deficit Disorder andHyperactivity; social isolation; occipital neuralgia; TMJ dysfunctionrelated symptoms; cognitive problems including memory disturbance;headaches (migraine and tension); peripheral neuropathy; as well asother conditions or disease states mentioned herein or any other diseaseor condition that may be treated with a cannabinoid.

It is an object of the present invention to provide a method for thetreatment of anxiety disorder; attention deficit disorder/poor focus;social isolation/autism-related symptoms; muscle tension and spasm;seizures and associated encephalopathy; headache; peripheral neuropathicpain and symptoms thereof; tinnitus/ringing in ears; sinus congestion;skin inflammatory conditions such as actinic keratosis; torticollis,dystonia; arthritis related pain and decreased range of motion;dizziness and light-headedness.

The above objects and others are attained by virtue of the presentinvention, which is directed in part to a method of treating a diseasestate or condition in a human patient via topical regionalneuro-affective (TRNA) or regional neuro-affective (RNA) therapy viaadministration of caryophyllene at the back of the neck region, or theback of the neck, e.g., at the hairline (BONATH). In certainembodiments, the method further includes administration of a secondtherapeutically active agent at the back of the neck at the hairline inclose proximity to and under or on the area of skin above the brain stemto provide regional neuro-affective therapy to the human patient. Incertain preferred embodiments, the caryophyllene is beta-caryophyllene.

In certain preferred embodiments, the caryophyllene is incorporated intoa pharmaceutically acceptable topical formulation along with a secondtherapeutically active agent (e.g., as described herein). In certainpreferred embodiments, the caryophyllene in the topical pharmaceuticalformulation are at a concentration from about 0.3% to about 20%, byweight. In certain embodiments, a unit dose of the topical formulationincludes from about 3 mg to about 200 mg caryophyllene. In certainpreferred embodiments, a unit dose of the topical pharmaceuticalformulation comprises from about 10 mg to about 50 mg caryophyllene, andmost preferably from about 15 mg to about 30 mg caryophyllene.

In certain preferred embodiments, the pharmaceutically acceptabletopical formulation comprises a topical aqueous-based carrier, with anoptional penetration enhancer.

In certain preferred embodiments, the method further comprises applyinga sufficient amount of the topical pharmaceutical formulation to theback of the neck region of the human patient such that the onset of atherapeutic effect occurs in less than about 30 minutes, or in less than15 minutes. The topical pharmaceutical formulation may be administered(applied to the back of the neck region) on a once a day basis, or on atwice a day basis, a three times a day basis, or on a four times a daybasis.

In certain embodiments, the patient is treated for a condition ordisease state selected from the group consisting of anxiety disorder;attention deficit disorder/poor focus; social isolation/autism-relatedsymptoms; muscle tension and spasm; seizures and associatedencephalopathy; headache; peripheral neuropathic pain and symptomsthereof; tinnitus/ringing in ears; sinus congestion; skin inflammatoryconditions such as actinic keratosis; torticollis, dystonia; arthritisrelated pain and decreased range of motion; dizziness andlight-headedness.

In certain embodiments, the patient is treated for a condition ordisease state selected from the group consisting of seizures,encephalopathy, spasticity, weakness, pain, numbness, anxiety,hypertension, Parkinson's disease, multiple sclerosis, and insomnia. Inother embodiments, wherein the patient is treated for a conditionselected from the group consisting of lethargy, focus/attentionalproblems, and cognitive issues. In other embodiments, the patient istreated for a condition selected from the group consisting ofradiculopathy and neuropathy. In yet other embodiments, the patient istreated for numbness, or a mood disorder.

In certain embodiments, the patient is treated for a condition ordisease state selected from the group consisting of ADD; ADHD; AnxietyDisorder; Cervical Spondylosis; Disc Herniations; Muscle Spasms; CentralPain Syndrome; Central Hypertension; acute pain; peripheral neuropathicpain; R.N. with Chronic Anxiety Disorder; PTSD; MS; seizures; headache;encephalopathy; lethargy; decreased spontaneity; gait disorder; autism;poor focus; tinnitus; myasthenia gravis; torticollis; chronic or acutesinus congestion; Eustachian tube blockage; fibromyalgia; Parkinson'sdisease; migraine; head or face injury; cervical laminectomy; thoraciclaminectomy; lumbar laminectomy; autism; cervical fusion; cerebralpalsy; spastic quadriparesis; vertebral artery dissection; posteriorfossa stroke: hemiparesis; nystagmus; opsillopsia; dysarthria; failedback syndrome; neonatal nuchal cord syndrome; chronic mood disorder;insomnia; tardive dyskinesia; cervical and/or thoracic compressionfracture; lumbar radiculopathy; impulsivity; trigeminal neuralgia;cervical spondylosis; muscle tension headaches; ischemic cerebrovasculardisease; eye twitching; lupus cerebritis; normal pressure hydrocephalus;bi-polar affective disorder; depression; and fatigue

In certain embodiments, the method further comprises further comprisestopically administering at the back of the neck region (e.g., BONATH)together with, sequentially, or simultaneously but in separateformulations, an additional drug(s) selected from the group consistingof: a cannabinoid(s), an anti-epileptic, an anxiolytic, a neuroleptic,an anti-psychotic, an analgesic, an anti-inflammatory, ananti-Parkinson's disease/syndrome drug, a drug for the treatment ofdystonia, a drug for the treatment of spastic conditions, a drug for thetreatment of benign essential/familial tremor, a drug for the treatmentof tremor related to MS, a drug for the treatment of chronicencepahalopathies, a drug for the treatment of congenital CNSdegeneration conditions/cerebral palsy, a drug for the treatment ofcerebellar degeneration syndromes, a drug for the treatment ofneuropathic and/or neurogenic pain, a drug for appetite suppression, adrug for neurodegenerative conditions, a drug for the treatment ofmultiple sclerosis, a drug for the treatment of insomnia, a drug for thetreatment of fatigue, a drug for the treatment of vertigo, nausea and/ordizziness, a drug for the treatment of writer's cramp and restless legsyndrome, other drugs which can beneficially be added to the treatmentin order to provide an additive or synergistic effect with respect totreating the patient's disease state or condition; and a combination ofany of the foregoing. In certain embodiments, the additional drug(s) isa dopamine agonist selected from the group consisting of apomorphine,pramipexole, ropinirole, bromocriptine, cabergoline, pergolide,rotigotine, entacapone, tocapone, seligiline, dopamine, and mixtures ofany of the foregoing. In other embodiments, the disease state orcondition is Parkinson's disease and/or related syndromes/diseases. Inother embodiments, the additional drug(s) is selected from the groupconsisting of the drug is a dopamine agonist, COMT inhibitors, MAO-Binhibitors, and mixtures of any of the foregoing. In other embodiments,the additional drug(s) is an anti-epileptic drug selected from the groupconsisting of Valproic acid, Leviteracetem, Lamotrigene, Topiramate,Pregabalin, Gabapentin, Carbamazepine, Oxcarbazepine, Phenobarbital andother barbiturates, Tiagabine, Retigabine, Lacosamide, Perampanel, andmixtures of any of the foregoing; or the additional drug(s) is ananxiolytic, a neuroleptic and/or an antipsychotic; or the additionaldrug(s) is an analgesic and/or an anti-inflammatory; or the additionaldrug(s) is used in the treatment of neuropathic and/or neurogenic pain;or the additional drug(s) is for multiple sclerosis; or the additionaldrug(s) is for insomnia; or the additional drug(s) is for fatigue; orthe additional drug(s) is for vertigo, nausea and/or dizziness; or theadditional drug(s) is for writer's cramp and restless leg syndrome; orthe additional drug(s) is a tricyclic antidepressant (TCA), atetracyclic antidepressant, or an atypical antipsychotic.

In certain preferred embodiments, the drug is formulated in apharmaceutically acceptable immediate release topical carrier. Incertain preferred embodiments, the topical carrier is aqueous based, andmay be a cream or gel.

In certain preferred embodiments, the method further comprisesformulating caryophyllene in a pharmaceutically acceptable immediaterelease aqueous-based carrier. In other embodiments, the caryophylleneis administered in a topical pharmaceutical formulation comprisingliposomes.

In certain preferred embodiments where the caryophyllene is administeredin a topical pharmaceutical formulation, the method further comprisesapplying a sufficient amount to the back of the neck region, e.g.,BONATH of the human patient such that the onset of clinical effectoccurs in less than about 30 minutes, and in certain preferredembodiments in less than about 15 minutes.

In certain preferred embodiments, the caryophyllene is incorporated intoa sustained release transdermal delivery system which is capable ofdelivering from about 10 mg to about 1000 mg through the skin of a humanpatient over a 24 hour period, the transdermal delivery system beingcapable of delivering the caryophyllene in such amounts for a timeperiod from about 1 to about 7 days.

In certain embodiments, the caryophyllene is administered viaimplantation or injection at the BONATH, or is administered viainjection in an immediate release pharmaceutically acceptable carrierfor injection. In certain embodiments, the caryophyllene is administeredvia injection or implantation in a controlled release carrier to providea prolonged effect of the caryophyllene. In certain embodiments, thecaryophyllene is administered to create a depot under the skin at theBONATH.

Certain embodiments of the invention are directed to a topicalformulation comprising a a pharmaceutically acceptable aqueous-basedcarrier, the caryophyllene being incorporated into the carrier in atleast one unit dose comprising from about 0.25 mg to about 80 mgcaryophyllene. Preferably, when applied in a unit dose to the back ofthe neck of the human patient the topical formulation provides an onsetof clinical effect occurs in less than about 30 minutes.

The invention is also directed to a topical formulation, comprisingcaryophyllene in a formulation suitable for administration at the backof the neck at the hairline in close proximity to and under or on thearea of skin above the brain stern of a human patient to provideregional neuro-affective therapy to the patient. The topical formulationmay be prepared as an immediate, controlled or sustained releaseformulation.

The drug formulations useful in the present invention may be in a formselected from a topical formulation (e.g, a cream, ointment or gel); atransdermal device; or an implantable or injectable formulation.

The invention is further directed to the use of caryophyllene in thepreparation of a medicament for providing regional neuro-affectivetherapy to a human patient, wherein the drug is administered at the backof the neck at the hairline in close proximity to and under or on thearea of skin above the brain stem to provide regional neuro-affectivetherapy to the patient.

In certain embodiments, caryophyllene is applied to the posteriorcervical region of the human in order to initiate the brainstem afferentstimulation therapy. Most preferably, the topical formulation or topicaltherapeutic system is applied to the back of the neck, preferably inclose proximity to or on the area of skin above the brain stem.

In other embodiments, caryophyllene is administered via implantation orinjection at the back of the neck, e.g., on the back of the neck at thehairline (BONATH). In such embodiments, the therapy is accomplished viathe availability of the drug(s) at the free nerve endings under theepidermis. In such embodiments, the drug may be incorporated into animplantation device or may be incorporated into a carrier such as a gelor matrix that will provide a prolonged release/effect of thecaryophyllene at the site. The carrier may be a hydrophilic orhydrophobic material, a colloidal material, and may be in a stateranging from a viscous liquid to a solid polymeric insert.

Certain embodiments of the invention are directed to a method oftreatment, comprising delivering caryophyllene through regionalneuro-affective therapy by application as a cream/gel or a sustainedrelease patch applied at the back of the neck, or via administrationunder the skin at the back of the neck via an implantable or injectabledrug formulation or device.

In certain embodiments, the method further provides for atherapeutically effective treatment through topical regionalneuro-affective (TRNA) therapy by application of a drug(s) (e.g.,caryophyllene) in a cream/gel or a sustained release patch applied atthe back of the neck without the side-effects and the other draw-backsof the current injection method.

In certain preferred embodiments, the caryophyllene is administered atthe back of the neck (e.g., BONATH) in an immediate release topicalformulation in a dose comprising from about 3 mg to about 200 mgcaryophyllene, and in certain embodiments more preferably from about 10to about 50 mg caryophyllene. In certain other embodiments, theimmediate release topical formulation includes from about 15 mg to about30 mg caryophyllene.

In certain preferred embodiments the caryophyllene comprises or consistsof β-caryophyllene.

In certain preferred embodiments, the method of treatment furthercomprises administering caryophyllene to other areas of the spine and/orperipheral nerves in addition to administration on or at the back of theneck, in order to provide an additive or synergistic effect and furthermodulate afferent neural input to the brain to affect efferent outflowfor relief of symptoms.

In certain preferred embodiments, the method of treatment furthercomprises topically administering at the back of the neck together with,sequentially, or simultaneously but in separate formulations, one ormore additional active agents (“drugs”) which may be chosen from thefollowing: a cannabinoid(s), an anti-epileptic, an anxiolytic, aneuroleptic, an anti-psychotic, an analgesic, an anti-inflammatory, ananti-Parkinson's disease/syndrome drug, a drug for the treatment ofdystonia, a drug for the treatment of spastic conditions, a drug for thetreatment of benign essential/familial tremor, a drug for the treatmentof tremor related to MS, a drug for the treatment of chronicencephalopathies, a drug for the treatment of congenital CNSdegeneration conditions/cerebral palsy, a drug for the treatment ofcerebellar degeneration syndromes, a drug for the treatment ofneuropathic and/or neurogenic pain, a drug for appetite suppression, adrug for neurodegenerative conditions, a drug for the treatment ofmultiple sclerosis, a drug for the treatment of insomnia, a drug for thetreatment of fatigue, a drug for the treatment of vertigo, nausea and/ordizziness, a drug for the treatment of writer's cramp and restless legsyndrome, and other drugs which can beneficially be added to thetreatment in order to provide an additive or synergistic effect withrespect to treating the patient's disease state or condition. In certainembodiments, for example, wherein the condition is insomnia and thesecond therapeutically active drug is melatonin; or the condition isADD/ADHD and the second therapeutically active drug is phentermine; orthe condition is Tourette's and the second therapeutically active drugsis phentermine; or the condition is DPN and the second therapeuticallyactive drug is 4-AP; or the condition is a peripheral neuropathiccondition and the second therapeutically active drug is 4-AP; or thecondition is spasticity and/or spasms and the second therapeuticallyactive drug is 4-AP; or the condition is migraine and/or tensionheadache and the second therapeutically active drug is a serotoninagonist; or the condition is Parkinson's disease, tremors, and/ordystonia and the second therapeutically active agent is apomorphine. Incertain embodiments the method further comprises administering at thesame site a third therapeutically active drug which is a skeletal musclerelaxant. In certain embodiments, in addition to caryophyllene, aserotonin agonist (e.g, sumatriptan) and a skeletal muscle relaxant(e.g., tizanidine) are administered for headache, migraine, or tensionheadache or the like.

For purposes of the present invention, the term “hack of the neck” or“hack of the neck region” is intended to encompass the entire area orregion extending from (behind) one ear to the other ear of the humanpatient and from the back of the head (i.e., above the neck) to belowthe hairline at the back of the neck of the human patient, i.e.,extending caudally from the back of the head at the hairline (“BONATH”)all the way down to the posterior extent of the back of the neck to thecervico-thoracic junction, located at C7 posterior spinous process (the“vertebra prominens”) of the human patient.

For purposes of the present invention, a “topical formulation” includes,for example, ointments, creams, lotions, pastes, gels, etc., whichreleases one or more drugs (e.g., cannabinoid drug(s)s) at apredetermined rate over a defined period of time to a defined site ofapplication.

For purposes of the present invention, an “injectable” formulationincludes, for example, an injectable solution, suspension, gel or thelike and may be in immediate release form or may provide a controlled orsustained release of the drug at the site of administration.

For purposes of the present invention, the term “immediate release”means that the caryophyllene is administered at the site of application(e.g., the back of the neck) and is available for immediate absorptionat the site of application. In other words, the term “immediate release”is meant to convey in terms of a topical formulation the fact that thereis nothing in the formulation (e.g., a sustained release carrier) thatwould delay or slow the availability of the drug at the site ofapplication (in contrast to, e.g., a transdermal device or patch).

For purposes of the present invention, an “implantable” formulationincludes, for example, a solid, semisolid or liquid drug formulationwhich can be administered at the back of the neck (e.g., BONATH) eithervia injection and/or via surgical implantation. The solid may comprisemicrospheres, microcapsules, pellets, discs, and the like. Theimplantable formulations of the invention may provide a controlled orsustained release of the drug at the site of administration.

For purposes of the present invention, a “transdermal therapeuticsystem” is defined as a drug-containing device (including e.g., patch,disc, etc.) which releases one or more drugs at a predetermined rateover a defined period of time to a defined site of application.

For purposes of the present invention, “transdermal” delivery is thedelivery by passage of a drug through the skin and into the bloodstream(“traditional” transdermal delivery) and is termed “transdermal systemicdrug delivery (TSD therapy).

For purposes of the present invention, the term “topical neuro-affectivetherapy” is synonymous with the more accurately termed topical regionalneuro-affective therapy (or “TRNA therapy”). This term describesimportant aspects of this delivery method: topical, regional (nearbrainstem and cervical spinal cord), and affecting the free nerveendings of the afferent nervous system, thereby not requiring thepresence of drug in the blood, as with systemic therapies which includesthe transdermal patch wherein the skin is used to have drug enter intothe bloodstream through a continuous application patch. In suchsituations, an ionotophoretic electric current generator may be requiredto cause drug entry into blood against a concentration gradient.

For purposes of the present invention “therapeutically effective” or“effective” amount is meant to be a nontoxic but sufficient amount ofcaryophyllene to provide the desired therapeutic effect.

For purposes of the present invention, an “effective” amount of apermeation enhancer as used herein, for example, means an amount thatwill provide the desired increase in skin permeability and,correspondingly, the desired depth of penetration, rate ofadministration, and amount of drug to be delivered.

For purposes of the present invention, the term “delivers” when usedwith respect to the topical formulation or transdermal therapeuticsystem means that the formulation or system provides a mean relativerelease rate or flux of the drug out of the formulation or system andthrough the skin of the patient.

By “predetermined area of skin” is intended a defined area of intactunbroken living skin. In certain embodiments of the present invention,the predetermined area will be in the range of about 1 cm2 to about 100cm2, preferably in the range of about 10 cm2 to about 100 cm2, morepreferably in the range of about 20 cm2 to about 60 cm2. However, itwill be appreciated by those skilled in the art of topical delivery thatthe area of skin through which drug is administered may varysignificantly, depending on the formulation, dose, the application ofthe formulation, and the like.

“Penetration enhancement” or “permeation enhancement” for purposes ofthe present invention relates to an increase in the permeability of skinto a pharmacologically active agent, i.e., so as to increase the rate atwhich the drug permeates through the skin and enters the bloodstream.The enhanced permeation effected through the use of such enhancers canbe observed by measuring the rate of diffusion of drug through animal orhuman skin using a diffusion cell apparatus.

For purposes of the present invention, the “brainstem afferentstimulation therapy region” is defined as the skin region of the headand/or at the frontotemporal region and/or upper posterior cervicalarea. In certain preferred embodiments, the treatment area is the postcervical area, in close proximity to the brain stem. Preferably thisarea is a relatively hairless area of the patient's head and/or neck.

For purposes of the present invention, the drug may be in the form ofthe base, or may be provided as a pharmaceutically acceptable salt(inorganic or organic) or complex. It may be in an optically pure formor a mixture of stereoisomers.

DETAILED DESCRIPTION

The therapeutically active agents used in the formulations and methodsof the invention comprise caryophyllene(s). Caryophyllene provides ameans of providing medical benefits of cannabinoids without negativeaspects of cannabis, legal or otherwise.

Caryophyllenes are known chemical compounds, Caryophyllene,or—β-caryophyllene, is a natural bicyclic sesquiterpene that is aconstituent of many essential oils, especially clove oil, the oil fromthe stems and flowers of Syzygium aromaticum, the essential oil ofCannabis sativa, rosemary, and hops. Caryophyllene is constituent ofessential oil extracts of clove, lavender, cinnamon, rosemary, basil,oregano, hops, black pepper, and several other plant and foodsubstances, including cannabis sativa. It is responsible for spicinessof black pepper, West African black pepper has highest concentration ofcaryophyllene, 60% of essential oil. It is usually found as a mixturewith isocaryophyllene and α-humulene, a ring-opened isomer.Caryophyllene is notable for having a cyclobutane ring, as well as atrans-double bond in an 8-membered ring, both rarities in nature.Beta-Caryophyllene (.beta.-Caryophyllene,trans-(1R,9S)-8-Methylene-4,11,11-trimethylbicyclo[7.2.0]undec-4-ene or[1R-(1R,4E,9S)]-4,11,11-trimethyl-8-methylene-bicyclo[7.2.0]undec-4-ene)is a natural bicyclic sesquiterpene compound.

Caryophyllene is FDA-approved as food additive and considered a dietarycannabinoid. A cannabinoid is any substance that activates humanendocannabinoid system (ECS), where cannabis or marijuana also acts.Cannabis plant contains some 100 different cannabinoids, of whichcannabidiol or CBD, is best known for medicinal effects. THC(tetrahydrocannabinol) is a cannabinoid which produces psychoactiveeffects, such as “high.” There are other naturally occurring substancesnot derived from cannabis that act on human endocannbinoid system. Theseare not considered illegal or regulated. Caryophyllene is such asubstance from plant or herbal sources. On the other hand, cannabis isillegal according to federal and some individual state laws.

Caryophyllenes are known to be useful in certain applications. Forinstance patent document U.S. Pat. No. 3,987,008 reveals sesquiterpenicderivatives as odor and taste-modifying agents; In J. Nat. Prod. 1992July; 55(7):999-1003, beta-caryophyllene and alpha-humulene are cited aspotential anticarcinogenic agents; in patent application WO alpha andbeta-humulene and (−)-beta-caryophyllene are cited in the control ofwhitefly species; in U.S. Pat. No. 5,314,693 alpha-humulene is cited asa repellent for pine wood nematodes; in patent application WO 02078719alpha and beta-caryophyllene are comprised in antitumor compositions.

The term “caryophyllene(s)” as used herein includes one or morecaryophyllene compounds (e.g., C15 terpenes including but not limited tobeta-caryophyllene), their salts, isomers, metabolites, pro-drugs,solvates (including hydrates) and adducts. For purposes of the presentinvention, the term “BCP” will mean beta-caryophyllene. When found innature, BCP (beta-caryophyllene) typically appears as a mixture of twopharmaceutically-active isomers E-BCP and Z-BCP, together withsubstantially inactive sesquiterpenes such as alpha-humulene andderivatives such as BCP oxide. Typically, natural sources include agreater proportion of E-BCP than Z-BCP. The caryophyllene compoundsuseful in the invention may comprise E-BCP, Z-BCP, and mixtures thereof,for example.

Over 100 different terpenes have been identified in the cannabis plant,and every strain tends toward a unique terpene type and composition. Theterpenes act synergistically with the cannabinoids to provide atherapeutic effect. Plant extracts are preferred as, in addition to oneor more cannabinoids, they will contain other chemical entities that mayprovide a beneficial effect either in their own right or in combinationwith the one or more cannabinoids. Such other chemicals include, forexample, volatile oils e.g. terpene or carotene rich volatiles. Knownterpenes present in the CMBE include C10 terpenes, e.g. mycerene, andpinenes and C15 terpenes e.g. caryophyllene.

Cannabis produces the majority of its active ingredients (cannabinoidsand terpenoids) in glandular trichomes found on the flowers, buds,leaves, and stalks of the plants. In preferred embodiments of thepresent invention, Cannabis plant material (e.g., flowers and leaves,either fresh or dried) containing glandular trichomes are processedmechanically to remove and concentrate the majority of these trichomes.Preferred processes separate the trichomes from the plant material bypassing the trichomes through a mesh of appropriate size to allow thetrichomes to pass through and exclude as much unwanted plant material aspossible. The mesh may be made of any suitable material, e.g., stainlesssteel, aluminum, nylon, etc.

In certain embodiments, beta-caryophyllene is obtained from Cannabis,hemp, marijuana (Cannabis sativa). In other embodiment,beta-caryophyllene is obtained from Commiphora gileadensis; BlackCaraway (Carum nigrum); Cloves (Syzygium aromaticum); Hops (Humuluslupulus); Basil (Ocimum spp.); Oregano (Origanum vulgare); Black pepper(Piper nigrum); West African Pepper (Piper guineense); Rosemary(Rosmarinus officinalis); True cinnamon (Cinnamomum zeylanicum); orMalabathrum (Cinnamomum tamala).

The endocannabinoid system (“ECS”) consists of a group of endogenouscannabinoid receptors located in mammalian brain and throughout thecentral and peripheral nervous systems. These entail neuromodulatorylipids and their associated receptors. As the body's “endogenous,”cannabinoid system, ECS is involved in a variety of physiologicalprocesses including neurological functions dealing with pain, mood,memory; and, movement, and sensation. The body's immune function andcell homeostasis is also maintained by ECS. It mediates the psychoactiveeffects of the cannabis (marijuana) plant. Cannabinoids are a diverseclass of compounds that include many of the unique compounds found inmarijuana.

Cannabinoids produce physiological and behavioral effects throughinteraction with specific membrane-bound receptors. Two primaryendocannabinoid receptors have been identified: CB1 and CB2. CB1receptors are found predominantly in brain (specifically in basalganglia and :limbic system, including hippocampus) and nervous system,as well as in peripheral organs and tissues. These are acted on by theendocannabinoid binding molecule Anandamide. Of G protein-coupled typereceptors (GPCR) in human brain, cannabinoid receptors are the mostplentiful. CB1 receptors responsible for euphoric and anti-convulsiveeffects of cannabis. CB2 receptors found only in peripheral nervoussystem appear responsible for anti-inflammatory effect such as painrelief. One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG),active at both CB1 and CB2 cannabinoid receptors. Its mimeticphytocannabinoid is cannabidiol (CBD), while that of Anandamide is THC,responsible for psycho-active effects. 2-AG and CBD are involved inregulation of appetite, immune system functions and pain management.

Caryophyllene acts on CB2 receptors. This represents potential therapyfor inflammation, pain, atherosclerosis, osteoporosis and otherconditions. In contrast to CB1 receptor, CB2 is not associated withpsychoactive effects. Beta-caryophyllene does not bind to the centrallyexpressed cannabinoid receptor type-1 (CB1) and therefore does not exertpsychomimetic effects.

In certain embodiments, the pharmaceutical formulations of the inventioninclude one or more “entourage compounds” in addition to thecaryophyllene. For the purposes of the invention, an entourage compoundis a compound that can increase the effects of one or morenaturally-occurring ligands that bind to one or more receptors, but thathas little or no affinity for the receptor. In a preferred, butnon-limiting embodiment, an entourage compound increases the effects ofa naturally-occurring ligand that binds to one or more cannabinoidreceptors, but that has little or no affinity for the cannabinoidreceptor.

In certain embodiments, the entourage compound included in thepharmaceutical formulations of the invention is a cannabinoid drug(s),such as by example and without limitation cannabidiol; cannabinodiol;cannabinol; delta8-tetrahydrocannabinol; delta9-tetrahydrocannabinol;cannabigerol; cannabichromene; cannabitriol; cannabicyclolol;cannabielsoin, cannabichromanone; cannabicoumaronone; cannabicitran;10-oxo-delta6a10a-tetrahydrocannabinol; cannabiglendol;delta7-isotetrahydrocannabinol; CBLVA; CBV; CBEVA-B; CBCVA;delta9-THCVA; CBDVA; CBGVA; divarinolic acid; quercetin; kaemferol;dihydrokaempferol; dihydroquercetin; cannflavin B; isovitexin; apigenin;naringenin; eriodictyol; luteolin; orientin; cytisoside; vitexin;canniprene; 3,4′-dihydroxy-5-methoxy bibenzyl; dihydroresveratrol;3,4′dihydroxy-5,3′-dimethoxy-5′-isoprenyl; cannabistilbene 1;cannabistilbene 11a; cannabistilbene 11b; cannithrene 1; cannithrene 2;cannabispirone; iso-cannabispirone; cannabispirenon-A;cannabispirenone-B; cannabispiradienone; alpha-cannabispiranol;beta-cannabispiranol; acetyl-cannabispirol;7-hydroxy-5-methoxyindan-1-spiro-cyclohexane;5-hydroxy-7-methoxyindan-1-spino cyclohexane;5,7-dihydroxyindan-1-cyclohexane; cannabispiradienone;3,4′-dihydroxy-5-methoxybibenzyl; canniprene; cannabispirone;cannithrene I; cannithrene 2; alpha-cannabispiranol;acetyl-cannabispirol; vomifoliol; dihydrovomifoliol; beta-ionone;dihydroactinidiolide; palustrine; palustridine; plus-cannabisativine;anhydrocannabisativine; dihydroperiphylline; cannabisin-A; cannabisin-B;cannabisin-C; cannabisin-D; grossamide; cannabisin-E; cannabisin-F;cannabisin-G; combinations of any of the foregoing; and the like.

In certain embodiments, the cannabinoid drug(s) is industrial hemp or anon-psychoactive hemp product.

In yet further embodiments, the cannabinoid drug(s) comprises a naturalcannabinoid compound, a synthetic cannabinoid compound, a semi-syntheticcannabinoid compound, or mixtures thereof. Illustrative of suchcompounds are cannabinoids or cannabinoid analogues selected from thegroup consisting of cannabinol, cannabidiol, delta9-tetrahydrocannabinol, delta 8-tetrahydrocannabinol,hydroxy-tetrahydrocannabinol, 11-hydroxy-9-tetrahydrocannabinol,levonantradol, delta 11-tetrahydrocannabinol, tetrahydrocannabivarin,dronabinol, amandamide, nabilone, a natural or synthetic analoguethereof, a natural or synthetic molecule with a basic cannabinoidstructure, and mixtures of any of the foregoing.

In certain embodiments, the cannabinoid drug(s) included in thetreatment and/or formulations of the present invention comprise a ligandthat binds to the CB₁ or the CB₂ receptor.

Cannabis terpenoids (e.g., limonene, myrcene, α-pinene, linalool,β-caryophyllene, caryophyllene oxide, nerolidol and phytol) share aprecursor with phytocannabinoids, and are all 19quale and fragrancecomponents common to human diets that have been designated GenerallyRecognized as Safe by the US Food and Drug Administration and otherregulatory agencies. Terpenoids are quite potent, and affect animal andeven human 19qualene when inhaled from ambient air at serum levels inthe single digits ng·M1-1. They display unique therapeutic effects thatmay contribute meaningfully to the entourage effects of cannabis-basedmedicinal extracts. Thus, in certain embodiments, the formulations andtreatments of the present invention include an active drug componentwhich comprises both a phytocannabinoid(s) and a terpenoid(s).Phytocannabinoid-terpenoid interactions may produce synergy with respectto treatment of pain, inflammation, depression, anxiety, addiction,epilepsy, cancer, fungal and bacterial infections (includingmethicillin-resistant Staphylococcus aureus)

Administration at the Back of the Neck

The caryophyllene formulations of the present invention are preferablyapplied at the back of the neck region of the human patient. In itsbroadest sense, the term “back of the neck” or “back of the neck region”is intended to encompass the area or region extending from (behind) oneear to the other ear of the human patient and from the back of the head(i.e., above the neck) to below the hairline at the back of the neck ofthe human patient, i.e., extending caudally from the back of the head atthe hairline (“BONATH”) all the way down to the posterior extent of theback of the neck to the cervico-thoracic junction, located at C7posterior spinous process (the “vertebra prominens”) of the humanpatient. More preferably, the administration of the caryophyllene islocated more directly at the back of the neck in the area above thecervical nerve roots, C1-C4 (and optionally including C5) such thatadministration of the caryophyllene is in the area at or above the skinwhere the afferent components of trigeminal nerve system, cervicalsympathetic nerves, and vagus nerve are located. In certain preferredembodiments, the back of the neck is more specifically the back of theneck at or around the hairline of the patient, which is an area moredirectly above the C1-C4 cervical nerve roots (this area is referred toherein as “BONATH”). It is to be understood that application at the backof the neck is not an exact art, and application of part or all of thedose in proximity to the back of the neck (e.g., behind the ears or onthe skin higher (on the back of the head) or lower (below the hairline,and even below the C5 area) than directly above the C1-C4 cervical nerveroots will still provide a therapeutically effective dose in accordancewith the invention; however, such locations are not optimal and maycause a lessening of the therapeutic effect or a delay in onset oftherapeutic effect. All such treatments are considered to fall withinthe definition of “back of the neck” for purposes of the presentinvention.

The administration of caryophyllene at the back of the neck is a novelway to deliver caryophyllene. This is believed to be accomplished byactivation of cutaneous afferent pathways through neuro-chemicalreceptors existing on free nerve-endings. The hypothesis of thistherapeutic modality is based on presence of numerous (hundreds ofthousands to millions) of free nerve-endings below the skin surface(stratum comeum) at upper posterior cervical region, the back of theneck or “nuchal” region. There exist at this location, directconnections through cervical nerve roots, C1-C4, and occasionally, C5,to afferent components of trigeminal nerve system, cervical sympatheticnerves, and vagus nerve providing significant input to CNS. At no otherlocation on the human body is such a magnitude of afferent neural inputaccessible through skin nerve-endings than here. Modulated CNS efferentneural outflow in response to afferent activation manifests asimprovement in clinical symptoms of MS and other conditions of brain andspinal cord impairment. By using direct nerve pathways, by-passing bloodflow and avoiding restrictions of “blood-brain-barrier,” onset oftherapeutic time is greatly reduced and systemic side effects areavoided.

The inventor has observed rapid therapeutic onset of action, generally,less than 10 to 15 minutes administration of caryophyllene at the backof the neck, with maximal benefit noted well within 30 minutes. Incertain embodiments, a prolonged therapeutic effect has been noted,e.g., about 4 to about 12 hours or more, depending on condition andseverity of the condition being treated.

The peripheral nervous system (PNS) communicates with central nervoussystem (CNS, consisting of brain, brainstem, and spinal cord) throughdorsal root ganglia which reside just outside the spine and act asneural relay areas between PNS and CNS. The human skin has free nerveendings just below the skin surface (stratum corneum), Which are theperipheral end components of spinal dorsal root ganglia. As skin and CNSare both derived from the same embryological tissue, neuro-ectoderm,receptors to neurotransmitters and other substances used in neuralcommunication are similarly represented on both free nerve endings andCNS. This makes sense as the skin needs to communicate directly with CNSwith respect to external stimuli. In fact, these receptors are on thecell surface of skin free nerve endings, making them readily accessibleto compounded drug applications to the skin for neural effect, “topicalneuro-affective therapy.” The binding of the topically administeredcaryophyllene to these receptors results in electrical action potentialgeneration and propagation to CNS, causing therapeutic effects to occur.As such, these same drug compounds do not need to enter the bloodstreamto reach their sites of activity, as it is with systemic delivery.Systemic side effects and drug activity at sites other than intended aretherefore not present. Further, by working through established neuralpathways than through the blood stream, the therapeutic effects arerapid, generally with 15-30 minutes or less. Many of the current drugsused systemically for peripheral conditions such as pain are thought towork by their effect on dorsal root ganglia, modulating neural impulsesto brain. With topical neuro-affective therapy the effects on dorsalroot ganglia. are direct and immediate as free nerve endings areperipheral extensions of the ganglia.

An important aspect of the benefits of “TRNA” or “RNA” therapy in CNSdrug delivery for brainstem related disorders lies in the anatomy of theregion. The free nerve endings with receptors for the neuro-chemicalsdopamine, serotonin, norepinephrine, and others are located just belowthe surface of the skin, easily assessable to drugs compounded in anappropriate dermal penetration enhancing medium and topically applied tothe skin.

To understand the concept of “peripheral neural afferent stimulationtherapy” as it applies to the brainstem and how topical drug delivery tothe back of the neck works requires a review of the neuro-anatomy andthe neuro-physiology of the region. As indicated above, this area of thenervous system is very complicated, compact and highly inter-active andinter-related.

The Trigeminal Nerve System is a component of the brainstem whichcoordinates pain input from the face, head, and the back of the neck. Assuch, it intimately influences the production of other symptomsassociated with syndromes attributed to dysfunction within thetrigeminal complex. These include the photophobia, phonophobia, nausea,anxiety, allodynia, and other focal sensory symptoms which may accompanya migraine attack. Similarly, episodes of trigeminal neuralgia (ticdouloreux) frequently involve significant affective (emotional) andvisceral components. Because of proximity and connections to otherstructures in the brainstem, abnormalities of temperature regulation,thirst, alertness, and mood are common. Some of these symptoms may be asequally disabling as the head and face pain.

In addition to receiving pain and sensory (afferent) input from theface, nasal and para-nasal sinuses, the teeth, scalp, the dura of theanterior and middle cranial fossa, the trigeminal system receivessimilar input from the soft tissues of the posterior cervical region.The free nerve endings in the back of the neck are just below thesurface of the skin, easily accessible to topically delivered drugsformulated in an appropriate dermal penetration enhancing compoundingmedium. The free nerve endings, via the small un-myelinated andmyelinated “C-fibers” (pain fibers) carry pain impulses through afferentsensory nerves back to the Trigeminal Nucleus Caudalis (TNC). TNC is thepain processing center extending from the pons through the entire extentof the brainstem to the upper cervical spinal cord. After synapsing atthe thalamus, pain impulses from TNC travel to the somatosensory cortex,where pain is perceived.

As providing important afferent input to the brain, the trigeminalsystem also receives afferent input from the rest of the body. Afferentinput is defined as any neural impulses coming back to the brain fromthe body. As such it provides information to the brain for processingand interpretation: pain, sensation, autonomic functions. Efferentoutput, on the other hand, consists of impulses originating in thecentral nervous system (brain, brainstem, and spinal cord) flowing tothe body for function: movement, response, action.

The vagus nerve includes both efferent and afferent fibers and isattached to the lower brainstem (medulla oblongata) via 8-10 radicles.The afferent fibers arise in the jugular and the nodose vagus ganglia.The somatic afferent fibers terminate in the nucleus of thetrigemino-spinal tract (TNC). Both the jugular and the nodose gangliaare connected with the superior cervical sympathetic gangion throughinter-communicating rami. The superior cervical sympathetic ganglion islocated between the internal carotid artery and the jugular vein on theventral aspects of the transverse processes of the 2^(nd), 3^(rd), andthe 4^(th) cervical vertebrae. It is the largest of the sympathetictrunk ganglia.

Sympathetic roots arising from the ganglion join the 1^(st) and the2^(nd) cervical nerves; frequently the 3^(rd), and occasionally, the4^(th). In addition to nerve fibers which extend rostrally from thesuperior cervical sympathetic ganglion, the sympathetic innervation ofthe head includes fibers which join the plexi on the common carotid andthe vertebrtal arteries. The one on the vertebral artery is continuouswith the plexus on the basilar artery. Rami derived from the internalcarotid plexus join the trigeminal nerve and the cavernous plexus inaddition to the other structures such as the abducens and deep petrosalnerves. From the cavernous plexus, located in the middle cranial fossa,sympathetic fibers join the oculomotor, trochlear, and the ophthalmicnerves. Fibers from the plexus also accompany blood vessels into thehypophysis. The spheno-palatine gangion, located in the pterygo-palatinefossa, receives sypmpathetic fibers from the face with rami distributedto the mucous membranes of the nares, mouth, the pharynx, and someorbital structures.

From the above, it is clear that cervical nerve function is intimatelyrelated to vagal afferents and afferents from the face, head, and thedura of cranial fossae associated with migraine and other head and facepain syndromes.

It has been long reported that vagal nerve stimulation (VNS) in the neckdown-regulates abnormal discharges from epileptic foci and treatsseizures. VNS is now approved as adjunct to medical therapy in certainforms of intractable epilepsy. It is also of benefit in severedepression resistant to traditional drug therapy. Studies with VNS inmigraine, anxiety, and fibromyalgia have been underway and have shownpreliminary promise in benefit. The mechanism of action appears to bethe down-regulation of hyper-excitable, dysfunctional neuronal systemsby increased inhibitory input to brainstem and associated connectionsthrough stimulation of the afferent system. Afferent stimulation, byfeed-back through TNC, causes reduction in efferent output from thebrainstem, resulting in resolution of clinical symptoms throughdown-regulation of hyper-active neuronal structures.

In the same way the electrical stimulation of VNS accomplishes itseffect on the brainstem, topical drug therapy to the posterior cervicalregion, in close proximity to the brainstem and its afferent inputs, istheorized to provide effect for the conditions mentioned above.

It is hypothesized that benefits of the present method of topical drugdelivery of central nervous system (CNS) active drugs lies in the factthat drug concentration gradients and blood flow factors are un-involvedin the therapeutic process. In contrast, the proposed delivery operatesthrough direct nerve connections between skin peripheral nerves at theback of the neck, for example at the hairline (BONATH) and brainstemstructures. Active drug compounded in an appropriate “dermal penetrationenhancing” medium topically applied to the skin at the back of neck haseffect on the free nerve endings of peripheral nerves locatedimmediately below the skin surface. Receptors to dopamine, serotonin,norepinephrine, and other neuro-transmitters/neuro-chemicals involvedwith neural transmission are located on these free nerve endings.Therefore, topically applied drug has near immediate therapeutic effectas direct neural impulses are involved—the concept of brainstem afferentstimulation through topical regional neuro-affective (TRNA) therapy. Allprior art and methods of drug delivery to the CNS have involved bloodflow and therapeutic drug blood level requirements. The inventive methoddoes not require such, which are the source of undesirable systemic andCNS side-effects. The present drug delivery process operates on theprinciple of an electrical capacitor whereas the prior relied on thosefluid dynamics and reservoir principles.

The factors which determine the success of TRNA therapy include: thedrug being considered, the compounding substance (surfactant/dermalpenetration enhancer), the disease process, and the location ofapplication. The free nerve endings in the skin at the back of the neckare important components of the cervical nerves with rich connections tothe trigeminal, vagal, and sympathetic systems communicating withbrainstem structures and other components of the central nervous system.These are the areas pain and other symptoms related to neuro-chemicalrelease are processed and perceived.

The skin at the upper part of the back of the neck, at the hairline, isinnervated by (supplied by nerves) the cervical nerve roots C1-3 thatare also part of the Trigeminal Nerve system of the brainstem. Thesecervical nerves (the wires) have their cell bodies (their generators)within the Nucleus Caudalis (Spinal Nucleus) of the Trigeminal Nerve inthe cervical spinal cord and the brainstem. Accordingly, they havedirect neural connections with brainstem processing areas. At the sametime, the peripheral nerve receptor sites for these nerves, the freenerve endings, reside under the skin surface at the back of the neck.The nerves in the soft tissues of the back of the neck, representing theC1, C2, and C3 segments of the cervical spinal cord are unique in thatthey have intimate connections with pathways directly affectingbrainstem and autonomic system function. There are direct connectionswith the Trigeminal Nerve system of the brainstem which provides forpain and other sensory input and interpretation from the head, face,sinus cavities, the dural covering of the brain, and the back of theneck. There are also connections with the vagus nerve and thesympathetic nervous system through the sympathetic ganglia. It isthrough these connections, which are nowhere else in the body asinter-related or at such close proximity to the surface of the humanskin, that the potential for the delivery of CNS acting drugs throughthe skin at the back of the neck (BONATH) is realized. Finally, skin isembryologically derived from neuro-ectoderm which is also responsiblefor the formation of the brain and other aspects of the CNS. Thus, thenerves in the human skin have a particularly direct relationship withthese structures. This provides for the efficacy noted with TRN/back ofthe neck therapy, At the same time, systemic and other CNS side-effectsare reduced or avoided. Thus, drugs topically applied to the skin inthis region have ready access to brainstem and other CNS structureswithout the requirement of drug in the bloodstream reaching targetsites.

In addition to the upper cervical nerves having direct relation to theTrigeminal Nerve System, they also contribute to the CervicalSympathetic Ganglia and the Vagal Nerve Systems through directconnections. These latter two systems provide some of the mostsignificant afferent feed-back to the brainstem and other portions ofthe CNS from the rest of the body. This allows for additional brainstemafferent stimulation potential through TRNA therapy at the back of theneck. Although skin at other areas of the face and head have eventualneural feed-back to the brainstem, the intimate connections to afferentfeed-back systems are lacking.

The question arises then: does TRNA therapy work with drug applicationto the forehead, face, or other regions of the head. The answer isperhaps—in some disease states such as migraine and face pain; but notas effective and efficient as at the back of the neck or at the back ofthe neck at the hairline (BONATH). Free nerve endings are also presentat these other locations but the distance back to involved brainstemstructures is greater and there is not the added advantage of richafferent neural connections to the trigeminal, vagal, and sympatheticnerve systems that are associated with the posterior cervical region.

TRNA therapy at the hack of the neck or at the BONATH delivery differsfrom traditional therapy (whether oral, injection, nasal spray,inhalation, or rectal) in that it has no reliance on the systemic orcerebral blood flow. Nor does it require therapeutic blood levels ofdrug. These latter factors are responsible for systemic and CNSside-effects as drug is delivered to areas not intended to be affectedin the therapeutic process. Transdermal systemic delivery by patch,although similarly applied to the skin as in TRNA therapy, differssignificantly in its reliance on a drug concentration gradient forabsorption into the systemic capillary and venous blood. TRNA therapy isunaffected by dermal vessels or systemic blood flow. It relies solely onthe function of the free nerve endings of cutaneous nerves and theirconnections at the point of application of compounded drug.

“Traditional” transdermal drug delivery by patch and TRNA are both“transdermal” in that in both, drug penetrates the skin (epidermis) foreventual clinical effect. The difference lies in the fact that in“traditional” transdermal patch therapy, drug enters the systemiccirculation through a concentration gradient and establishes atherapeutic drug blood level. Although measuring a blood level givesassurance drug is being taken or delivered systemically, allowing forchecking compliance, it is also the source of undesirable side-effectsand drug interactions. Of necessity, with systemic transdermal patchtherapy, drug applied to the skin surface must be absorbed through thesmall vessels in the dermis for eventual presence in the systemic venousblood for measurement of drug level. With TRNA therapy, thecaryophyllene need only be available at the free nerve endings under theepidermis. No concentration gradients or systemic blood levels arenecessary. Drug delivery is unaffected by cardiac output or cerebralblood flow factors. Of significance, persons afflicted with Parkinson'sdisease are typically elderly with concomitant cardiac and cerebralvascular disease.

Thus, in certain embodiments, the methods and formulations of theinvention deliver an amount of caryophyllene in the TRNA therapy thatwould provide sub-therapeutic plasma levels if administered orally, butwhich is therapeutically effective when administered via TRNA therapy atthe back of the neck or at the BONATH.

It is hypothesized by the inventor that a principal reason TRNA therapyis rapid in the onset of clinical effect (e.g., less than about 10-15minutes) for is that it operates through an “electro-chemical” process.Active drug compounded in an appropriate dermal penetration enhancingmedium acts at free nerve endings, changing the neurochemistry ofreceptors at the neural synapse: apomorphine (dopamine andnorepinephrine agonist), increasing dopamine and. norepinephrine levelsand improving neural transmission. After a point of receptorstimulation, neural (electrical) impulses are generated back to neuronalcell bodies residing in the spinal cord and brainstem: “afferentfeed-back”. The nervous system functions through neurons generatingelectrical impulses and the release of neurochemicals/neuro-transmitters(serotonin, norepinephrine, dopamine, and acetylcholine, being the majorones) at neural receptor sites called “synaptic clefts”. Accordingly,the process in TRNA therapy may be considered analogous to an electricalcapacitor discharging to perform a function, such as turning on a lightswitch. Viewed from this perspective, the rapid onset of clinical effectobserved in TRNA therapy makes sense.

Alternatively, transdermal systemic patch delivery operates on theprinciples of chemical gradients and fluid dynamics. These processeshave variability and inherent idiosyncrasies, fluctuating heart functionas a pump for blood flow being one. Thus, despite the advantage ofmeasurable drug levels, a more circuitous route with slower clinicaleffect is observed. This makes systemic transdermal patch deliveryinappropriate for acute therapy.

Therapeutic Applications

Potential clinical applications of caryophyllene applied at the back ofthe neck in accordance with the present invention include the following:seizures; epilepsy; encephalopathy, including lethargy,focus/attentional problems, and cognitive issues; spasticity; weakness(e.g., muscle weakness); pain, including radiculopathy and neuropathy,lower back pain, and fibromyalgia; neuropathic pain; numbness and/ortingling; anxiety and other mood disorders; hypertension and autonomicdysfunction; Parkinson's disease and tremors, including EssesntialTremor; insomnia; Bell's palsy and facial nerve dysfunction; glaucoma(marijuana is known to reduce pressure in the eye); multiple sclerosis(an extract that relieves pain and muscle spasms in MS patients has beenapproved in Europe and Canada, though not in the U.S. (Nabiximols, tradename Sativex, an aerosolized mist for oral administration containing 1:1ratio of CBD and THC)), AIDS (one of the FDA-approved synthetic versionsof a substance found in marijuana, (−) -trans-Δ⁹-tetracydocannabinol(generally referred to as dronabinol) helps increase appetite and treatweight loss in patients with the disease); cancer (dronabinol is alsomarketed in the U.S. to treat nausea associated with chemotherapy;researchers have reported CBD's ability to “turn off” the activity ofID1, a gene responsible for metastasis in breast and other types ofcancers, including aggressive triple negative breast cancer; PTSD;trigeminal neuralgia; hemi-facial spasms; Autism/Asperger's; AttentionDeficit Disorder and Hyperactivity; social isolation; occipitalneuralgia; TMJ dysfunction related symptoms; cognitive problemsincluding memory disturbance; headaches (migraine and tension);peripheral neuropathy; Dravet syndrome (an intractable seizure disorderalso known as Severe Myoclonic Epilepsy of Infancy (SMEI)—an oral CBDformulation received orphan drug status in US as treatment for thiscondition); apnea (including central sleep apnea, obstructive sleepapnea syndrome, and mixed apneas (having components of central andobstructive sleep apneas); smoking cessation; arthritis, includingrheumatoid arthritis; depression; emesis; anti-obesity; nausea;vomiting; alcohol use disorders; dystonia; inflammatory bowel syndrome;neuropathic pain associated with post-herpetic neuralgia; diabeticneuropathy; shingles; burns; actinic keratosis; oral cavity sores andulcers; post-episiotomy pain; psoriasis; pruritis; contact dermatitis;eczema; bullous dermatitis herpetiformis; exfoliative dermatitis;mycosis fungoides; pemphigus; severe eryththema multiforme; seborrheicdermatitis; ankylosing spondylitis; psoriatic arthritis; Reiter'ssyndrome; gout; chondrocalcinosis; joint pain; dysmenorrhea;musculoskeletal pain; molymyositis; bursitis; epicondylitis;osteoarthritis; synovitis; pancreatitis; and other disease states andconditions which will be apparent to those skilled in the art.

In certain preferred embodiments, the topical caryophyllene afferentneural activation therapy of the invention is used for the treatment ofanxiety disorder; attention deficit disorder/poor focus; socialisolation/autism-related symptoms; muscle tension and spasm; seizuresand associated encephalopathy; headache; peripheral neuropathic pain andsymptoms thereof; tinnitus/ringing in ears; sinus congestion; skininflammatory conditions such as actinic keratosis; torticollis,dystonia; arthritis related pain and decreased range of motion;dizziness and light-headedness.

In certain preferred embodiments, the topical caryophyllene isformulated in a vehicle that allows for the drug to be immediatelyabsorbable and available for the free nerve endings of the trigeminalnervous system which reside under the skin surface at the back of theneck when the formulation is, e.g., applied to the back of the neck of ahuman patient in the form of a cream, gel or ointment. On the otherhand, it is contemplated in certain embodiments of the invention thatthe topical or implantable caryophyllene formulation can be administeredin the form that provides a prolonged release at the back of the neck,for example, in the form of a transdermal patch. The uniqueness of thisparticular area of the human anatomy which allows this delivery methodto work. In further embodiments, the caryophyllene is applied (i) in atopical form that provides a therapeutically effective dose of thecaryophyllene immediately absorbable at the site (back of the neck), and(ii) a further therapeutically effective dose(s) in a prolonged orsustained release formulation (e.g., a transdermal patch or contained inliposomes) that releases the caryophyllene over time such that thecaryophyllene is absorbed at the back of the neck in therapeuticallyeffective amounts over a span of multiple dosage time intervals (e.g.,1-7 days).

A unit dose of the topical formulation(s) of caryaophyllene drug(s) usedin accordance with the present invention preferably includes from about10 mg to about 200 mg caryophyllene. In certain preferred embodiments, aunit dose of the topical caryophyllene formulation provides acaryophyllene dose from about 3 mg to about 200 mg, and in certainembodiments more preferably from about 10 mg to about 50 mg or fromabout 15 mg to about 30 mg. This may be administered, e.g., in a topicalcream, ointment, gel or the like. A representative topical formulationmay include from about 0.3% to about 20% caryophyllene, and morepreferably from about 1% to about 5% caryophyllene. In certain preferredembodiments the caryophyllene comprises or consists of β-caryophyllene.

In certain embodiments, the topical caryophyllene formulation of thepresent invention is administered at the back of the neck on the humanpatient and a therapeutic effect is preferably provided within about 45minutes, preferably within about 30 minutes, or 25 minutes, or 20minutes, or 15 minutes, or 10 minutes after the administration. Incertain preferred embodiments, a therapeutic effect is noticed withinabout 10 to about 15 minutes after the administration (e.g., applicationof the topical formulation to the back of the neck).

In certain embodiments, the topical caryophyllene formulation isadministered on an “as needed” basis. In other embodiments, the topicalcaryophyllene formulation is administered on a once a day basis, or on atwice a day basis, or on a three times a day basis, or on a four times aday basis.

The treatment is dependent on disease state/condition treated. Forchronic disease states/conditions (such as seizures, neuropathies,autism/encephalopathies, etc.) the topical treatment (e.g., unit dose oftopical caryophyllene applied to the back of the neck in accordance withthe invention) can be via a 1-4 times per day, preferably 2-3 times perday application, long-term. For acute disease states/conditions orsubacute disease states/conditions (such as back or neck injuries,migraine attack, panic states, and others), the topical treatment may beadministered as needed, e.g. up to 1-4 times per day over the durationof symptoms. Relief of symptoms for acute and sub-acute conditions maybe achieved anywhere from just one applicator with partial or completerelief to few days with partial or complete relief, and repeated withrecurrence.

For example, the topical formulation may be administered as a unit dosein an amount from about 0.5 g to about 1 g at a caryophylleneconcentration from about 0.1% to about 5% (or more)

Combination Therapy

In certain preferred embodiments of the invention, the caryophyllene(s)is administered together with (e.g., in the same formulation), orsimultaneously (but separately) or sequentially with an additionalactive agent(s) (“drug(s)”) suitable for treating the patient's diseasestate or condition. Classes of drugs which would be suitable as anadditional active agent(s) include, but are not limited to:

-   -   1. Anti-Epileptic drugs: Examples of a second therapeutic        agent(s) include Valproic acid (Depacon®/Depakot® e),        Leviteracetem (Keppra®), Lamotrigene (Lamictal®), Topiramate        (Topamax®), Pregabalin (Lyrica®), Gabapentin (Neurontin®),        Carbamazepine (Tegretol®), Oxcarbazepine (Trileptal®),        Phenobarbital and other barbiturates, Tiagabine (Gabatril®),        Retigabine™ (Valeant Pharmaceuticals), Lacosamide® (Schwarz        Biosciences), and Perampanel® (Eisai) are in development as        anti-epileptics and neuromodulators for other associated        neurological, pain, and psychiatric conditions.    -   2. Anxiolytic drugs: Benzodiazepines: Examples of a second        therapeutic agent(s) include lorazepam (Ativan®), diazepam        (Valium®), clonazepam (Klonopin®), chlordiazepoxide (Librium®),        and alprazolam (Xanax®).    -   3. Neuroleptics/Anti-Psychotic drugs: Examples of a second        therapeutic agent(s) include chlorpromazine (Thorazine®),        haloperidol (Haldol®), risperidone (Risperdal®), olanzapine        (Zyprexa®) and quetiapine (Seroquel®).    -   4. Analgesics/Anti-Inflammatory drugs: Examples of a second        therapeutic agent(s) include prednisone, solumedrol, and other        steroids, naproxen, aspirin, acetaminophen, voltaren,        ketoprofen, ibuprofen, other NSAID's.    -   5. Parkinson's Disease/Similar or Related Syndrome (e.g.,        tremors, spasticity and spasms, dystonia) drugs: Examples of a        second therapeutic agent(s) include dopamine agonists such as        apomorphine.    -   6. Dystonia (cervical and otherwise), which sometimes occur in        conjunction with spasmdic torticollis and spastic conditions:        Examples of a second therapeutic agent(s) include dopamine        agonists such as apomorphine.    -   7. Benign essential/familial tremor, tremor related to MS,        chronic encepahalopathies such as from stroke or head injuries,        congenital CNS degeneration conditions/cerebral palsy,        cerebellar degeneration syndromes, and spasicity conditions from        the above: Examples of a second therapeutic agent(s) of a second        therapeutic agent(s) include dopamine agonists such as        apomorphine.    -   8. Neuropathic/Neurogenic pain drugs: Examples of a second        therapeutic agent(s) include carbamazepine, gabapentin,        topiramate, zonisamide, phenytoin, desipramine, amitriptyline,        imipramine, doxepin, protriptyline, pentoxifylline, and        hydroxyzine.    -   9. Smoking Cessation drugs: Examples of a second therapeutic        agent(s) include drugs such as varenicline.    -   10. Appetite Suppressant drugs: Examples of a second therapeutic        agent(s) include drugs such as Sibutramine.    -   11. Neurodegenerative Diseases: Examples of a second therapeutic        agent(s) include Aricept/donepezil, Exelon/rivastigmine,        Reminyl/Razadyne/galantamine, and Namenda/memantine and their        naturally occurring counterparts, as well as NMDA antagonists.

12. Multiple Sclerosis (MS): Examples of a second therapeutic agent(s)include drugs such as 4-aminopyridine.

13. Insomnia: Examples of a second therapeutic agent(s) include drugssuch as zolpidem or melatonin.

14. Fatigue: Examples of a second therapeutic agent(s) include drugssuch as pemoline and Modafinil.

15. Vertigo, Nausea and/or Dizziness: Examples of a second therapeuticagent(s) include drugs such as as meclizine, dimenhydrinate,prochlorperazine, scopolamine and diphenhydramine.

16. Writer's cramp and restless leg syndrome: Examples of a secondtherapeutic agent(s) include dopamine agonists such as apomorphine.

17. Migraine: examples of a second therapeutic agent(s) includeserotonin agonists, such as sumatriptan; ergot alkaloids such asergotamine; skeletal muscle relaxants such as tizanidine; andcombinations of any of the foregoing.

18. Muscle spasms and spasticity: examples of a second therapeuticagent(s) include skeletal muscle relaxants such as tizanidine, as anorepinephrine alpha-adrenergic receptor agonist; 4-amino pyridine, withagonist and antagonist activities at neurochemical receptor sitesaffecting glutamate, dopamine, serotonin function in CNS, as well asthat of other neurotransmitters to improve nerve conduction, reducespasticity, and improve neurological function in multiple sclerosis, MS,stroke; and brain and spinal cord injuries.

19. Peripherally applied, topical 4-amino pyridine found useful indiabetic peripheral neuropathy, DPN, and other peripheral neuropathicconditions.

20. ADD/ADHD and/or Tourette's syndrome: an example of a secondtherapeutic agent(s) would be phentermine.

21. Anxiety and/or panic attacks and/or mood disorders: an example of asecond therapeutic agent(s) is milnacipran.

In certain embodiments, the additional drug(s) includes a dopamineagonist such as apomorphine (Apokyn®, APO-go®), pramipexole(Mirapexin®), ropinirole (Requip®), bromocriptine (Parlodel®),cabergoline (Cabaser®, Dostinex®), pergolide (Permax®, Celance®)rotigotine (Neupro®), mixtures of any of the foregoing, or otherdopamine agonists known to those skilled in the art. One skilled in theart will appreciate that dopamine agonists other than apomorphine may beused in the formulations and methods of the present invention, and allsuch agents are meant to be encompassed by the term “dopamine agonists.”For example, such drugs include, but are not limited to, carbidopa(Sinemet®), dopamine agonists (Requip®, Rotigotine®, Mirapex®), COMTinhibitors (Entacapone®, Tocapone), rasagiline (Azilect®) (MAOinhibitors) and MAO-B inhibitors (Selegiline (Eldepryl®). In certainpreferred embodiments, the concentration of dopamine agonist included inthe topical unit dose is from about 0.25 mg to about 4 mg, based onapomorphine, or an therapeutically equivalent amount of another dopamineagonist as described herein.

In other embodiments, the additional drug(s) includes an opioid such asmorphine, codeine, dihydrocodeine, hydrocodone, hydromorphone,nicomorphine, oxycodone, oxymorphone fentanyl, alphamethylfentanylalfentanil sufentanil, remifentanil, carfentanyl, ohmefentanyl,thebaine, oripavine, diacetylmorphine (heroin), phenylpiperidines suchas pethidine (meperidine) and ketobemidone, allylprodine, prodine,propoxyphene dextropropoxyphene, dextromoramide, bezitramide,piritramide, methadone, dipipanone, levomethadyl Acetate (LAAM),loperamide, diphenoxylate, dezocine, pentazocine, phenazocine,buprenorphine, dihydroetorphine, etorphine butorphanol, nalbuphine,levorphanol, levomethorphan, lefetamine, meptazinol, tilidine, tramadol,tapentadol, mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is tarpentadol (acentrally acting oral analgesic having two mechanisms of actioncombining mu-opioid receptor agonism and norepinephrine reuptakeinhibition).

In yet other embodiments, the additional drug(s) is a selectivenorepinephrine reuptake inhibitor, such as Atomoxetine (Strattera®),Mazindol (Mazanor®, Sanorex®), Nisoxetine (LY-94939), Reboxetine(Edronax®, Vestra®), Viloxazine (Vivalan®), mixtures thereof, and thelike.

In yet other embodiments, the additional drug(s) is a benzodiazepine,such as lorazepam (Ativan®), diazepam (Valium®), clonazepam (Klonopin®),chlordiazepoxide (Librium®), alprazolam (Xanax®), temazepam (Restoril®),mixtures thereof, and the like. In other embodiments, the drug is aneuroleptic or psychotropic such as chlorpromazine (Thorazine®),haloperidol (Haldol®), risperidone (Risperdal®), olanzapine (Zyprexa®)and quetiapine (Seroque®).

In other embodiments, the additional drug(s) is an agent that treatsdepression and/or anxiety, for example, selective serotonin reuptakeinhibitors (SSRIs) such as fluoxetine (Prozac), sertraline (Zoloft®),venlafaxine (Effexor®), citalopram (Celexa®), parocetine (Paxil),mixtures thereof, and the like (such as trazodone (Desyrel)), and/orserotonin-norepinephrine reuptake inhibitors (SNRI), such asDesvenlafaxine (Pristig®), Duloxetine (Cymbalta®), Milnacipran (Ixel®,Savella®), Venlafaxine (Effexor®), mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is anorepinephrine-dopamine reuptake inhibitor (NDRI), such as Amineptine(Survector®), an aminoketone antidepressant such as Bupropion(Wellbutrin®, Zyban®), Dexmethylphenidate (Focalin), Methylphenidate(Ritalin®, Concerta®), Nomifensine (Merital®), a phenylpiperazineantidepressant such as nefazodone (Serzone®), a piperazino-azepineantidepressant such as mirtazapine (Remeron®), mixtures thereof, and thelike.

In yet other embodiments, the additional drug(s) may be an NMDA receptorantagonist. Phencyclidine, ketamine, and dextromethorphan, are used asrecreational drugs. At subanesthetic doses, however, these drugs havemild stimulant effects, and these agents have shown promise for thetreatment of conditions that involve excitotoxicity, including traumaticbrain injury, stroke, and neurodegenerative diseases such asAlzheimer's, Parkinson's, and. Huntington's.

Additionally, the additional drug(s) may be an agent that treatsneuropathic/neurogenic pain (pain that arises from nerve dysfunction andriot as a result of injury, e.g., trigeminal neuralgia), such ascarbamazepine, gabapentin, topiramate, zonisamide, phenytoin,desipramine, amitriptyline, imipramine, doxepin, protriptyline,pentoxifylline, and hydroxyzine.

In other embodiments, the additional drug(s) treats insomnia, such aszolpidem (Ambien®).

In other embodiments, the additional drug(s) treats fatigue. Such drugsinclude centre nervous system stimulants such as pemoline (Cylert®) andModafinil (Provigil®).

In yet other embodiments, the additional drug(s) treats vertigo, nauseaand/or dizziness, such as meclizine (Antivert®), dimenhydrinate(36qualene36), prochlorperazine (36qualene36®), scopolamine (Transderm®)and diphenhydramine (Benadryl®).

In yet other embodiments, the drug is a serotonin-norepinephrinereuptake inhibitor (SNRI), such as Desvenlafaxine (Pristiq®), Duloxetine(Cymbalta®), Milnacipran (Ixel®, Savella®), Venlafaxine (Effexor®),mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is a tricyclicantidepressant (TCA), such as Amitriptyline (Elavil®), Butriptyline(Evadene®, Evadyn® e), Clomipramine (Anafranil®), Desipramine(Norpramin®, Pertofrane), Dosulepin (Prothiade), Doxepin (Adapin,Sinequan), Imipramine (Tofranil®), Lofepramine (Feprapax®, Gamanil®,Lomont®), Nortriptyline (Aventyl®, Nortrilen®, Pamelor®), Protriptyline(Vivacti® l), Trimipramine (Surmontil®), mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is a tetracyclicantidepressant, such as Amoxapine (Asendin®), Maprotiline (Ludiomil®),Mianserin (Tolvon®), mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is an atypicalantipsychotic, such as Ziprasidone (Geodon®, Zeldox®), Nefazodone(Serzone®), and the like.

In yet other embodiments, the additional drug(s) is an anti-convulsantor anti-epileptic drug such as arylsulfonimide analogues such asAcetazolimide (Diamox)®, tricyclic iminostilbene derivatives such ascarbamazepine (Tegreto®), benzodiazepines such as clonazepam(Klonopin®), clorazepate dipotassium (Tranxene®), lorazepam (Ativan®)and diazepam (Valium®), carboxylic acid derivatives such as valproicacid (Depakene®) and divalproex sodium (Depakote®), succinimidederivatives such as ethosuximide (Zarontin®), carbarnate esters of2-phenyl-1,3-propanediol such as felbamate (felbatol®), hydantoins suchas phenytoin (Dilantin®), phenytoin sodium (Dilantin®) and fosphenytoinsodium (Cerebyx®), structural analogues of GABA such as gabapentin(Neurontin®) and pregabalin (Lyrica®), phenyltriazines such aslamotrigine (Lamictal®), pyrrolidine derivatives such as levitiracetam(Keppra®), tricyclic iminostilbene derivatives such as 37qualene37pine(Trileptal), barbiturates such as Phenobarbital, desoxybarbiturates suchas primidone (Mysoline®), nipecotic acid derivatives such as tiagabinehydrochloride (Gabitril®), sulfamated monosaccharides such as topiramate(Topamax®), oxazolidinedione derivatives such as trimethadione(Tridione®), and methanesulfonamides such as zonisamide (Zonigran®).Additional drugs such as Retigabine® (Valeant Pharmaceuticals),Lacosamide® (Schwarz Biosciences), and Perampanel® (Eisai) are indevelopment as anti-epileptics and neuromodulators for other associatedneurological, pain, and psychiatric conditions, and thus are furtherexamples of potentially useful drugs in the present invention.

In yet other embodiments, the additional drug(s) is ananalgesic/anti-inflammatory agent such as acetaminophen; prednisone,solumedrol, and other steroids; naproxen, aspirin, voltaren, ketoprofen,ibuprofen, nabumetone, and other NSAID's. The NSAID may be COX-1, COX-2or mixed COX-1/COX-2 inhibitors. Examples of COX-2 inhibitors includeoxicam, meloxicam, and the more selective celecoxib, rofecoxib,valdecoxib, parecoxib and etoricoxib. Further examples ofcorticosteroids include methylprednisolone, prednisolone, dexamethasone,and adreno-corticotrophic hormone (ACTH), corticotropin.

Additionally, the additional drug(s) may be an agent that treatsneuropathic/neurogenic pain (pain that arises from nerve dysfunction andnot as a result of injury, e.g., trigeminal neuralgia), such ascarbamazepine, gabapentin, topiramate, zonisamide, phenytoin,desipramine, amitriptyline, imipramine, doxepin, protriptyline,pentoxifylline, and hydroxyzine, mixtures thereof, and the like.

In other embodiments, the additional drug(s) is 4-aminopyridine (4-AP;also known as Fampridine®) or a pharmaceutically acceptable andtherapeutically active derivative thereof. This drug has been shown tohave the ability to improve the communication between damaged nerves,which may result in increased neurological function in the treatment ofconditions such as multiple sclerosis (MS). An example of another suchdrug is 3,4 diaminopyridine. In certain preferred embodiments, the 4-APis included in the formulation in an amount from about 1 mg to about 40mg, preferably about 2 to about 10 mg, and in certain embodiments mostpreferably about 5 mg.

In other embodiments, the additional drug(s) is useful for the treatmentof Dementia/Alzheimer's disease, such as Aricept®/donepezil,Exelon®/rivastigmine, Reminyl®/Razadyne®/galantamine, andNamenda®/memantine, their naturally occurring counterparts, and mixturesthereof.

In other embodiments, the additional drug(s) is a serotonin agonistuseful for the treatment of migraine, such as for example and withoutlimitation, sumatriptan, naratriptan, eletriptan, rizatriptan,zolmitriptan, almotriptan, frovatriptan, pharmaceutically acceptablesalts thereof, mixtures thereof, and derivatives thereof. Preferably theserotonin agonist is sumatriptan(3-(2-(dimethylamino)ethyl)-N-methyl-1H-indole-5-methanesulfonamide),one of its salts or derivatives. For migraine use, the additionaldrug(s) may further comprise an ergot alkaloid, such as for example andwithout limitation bromocriptine, ergocristine, ergocristinine,ergotamine, ergotaminine, ergocryptine, ergocryptinine, ergocornine,ergocorninine, ergosine, ergosinine, ergonovine, ergometrinine,dihydroergotamine, lisuride, d-lysergic acid, d-isolysergic acid,lysergol, lergotrile, metergoline, methysergide, methylergonovinepharmaceutically acceptable salts thereof, mixtures thereof, andderivatives thereof. Preferably the ergot alkaloid is ergotamine,dihydroergotamine, methysergide, salts, derivatives, active metabolitesor prodrugs thereof e.g., dihydroergotamine mesylate. As used herein,the identification of an agent(s) to be delivered includes not only theergot alkaloid per se but also its topically administrable prodrugs,active metabolites and prodrugs of the active metabolites.

In certain embodiments of the present invention, the serotonin agonistis in an amount of from about 0.5 mg to about 200 mg, preferably theserotonin agonist is in an amount of from about 0.5 mg to about 100 mg,and most preferably from about 10 mg to about 100 mg. In certainpreferred embodiments, the formulations of the present invention containsumatriptan base or a pharmaceutically acceptable salt thereof (e.g.,sumatriptan succinate). When the serotonin agonist is sumatriptan or apharmaceutically acceptable salt thereof, the amount of sumatriptan isin an amount of from about 0.5 mg to about 200 mg, preferably in anamount of from about 5 mg to about 200 mg, from about 5 mg to about 100mg, from about 5 mg to about 50 mg, or from about 5 mg to about 25 mg,and most preferably is in an amount of 12.5 mg, 25 mg, 50 mg or 100 mg.Comparative oral doses of certain triptans are as follows: sumatriptan,50 mg; rizatriptan, 10 mg; naratriptan, 2.5 mg; zolmitriptan, 2.5 mg;and eletriptan, 40 to 80 mg. Therefore, one skilled in the art canreadily determine therapeutically equivalent doses of serotonin agoniststhat may be useful in the present invention.

In other embodiments, the additional drug(s) is a skeletal musclerelaxant. Useful skeletal muscle relaxants include centrally actingskeletal muscle relaxants, and are not limited to for example andwithout limitation, afloqulone, baclofen, botulin toxins, carisoprodol,chlormezanone, chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine,clonazepam, diazepam, eperisone, idrocilamide, inaperisone, mephenesin,mephenoxalone, methocarbamol, metaxalone, mivacurium chloride,orphenadrine, phenprobamate, pridinol mesylate, quinine, tetrazepam,thiocolchicoside, tizanidine, tolperisone, pharmaceutically acceptablesalts thereof, active metabolites thereof, prodrugs thereof and mixturesthereof. Preferably the skeletal muscle relaxant is tizanidine base,tizanidine hydrochloride or any pharmaceutically acceptable saltsthereof, prodrugs thereof or mixtures thereof. In certain preferredembodiments where the skeletal muscle relaxant is tizanidine, the amountof tizanidine included in the formulation is from about 1 mg to about 10mg, preferably about 5 mg. One skilled in the art can readily determinetherapeutically equivalent doses of other skeletal muscle relaxants suchas those mentioned herein that may be useful in the present invention.

In certain embodiments, the topical formulation is used to treatinsomnia, and a therapeutically effective amount of caryophyllene and atherapeutically effective amount of melatonin. The therapeuticallyeffective amount of melatonin may be, for example, from about 0.05 mg toabout 30 mg, and in certain preferred embodiments about 5 mg.

In certain embodiments, the topical formulation is used to treatParkinson's disease, tremors and/or dystonia. In such embodiments, thetopical formulation comprises a therapeutically effective amount ofcaryophyllene and a therapeutically effective amount of apomorphine. Thetherapeutically effective amount of apomorphine may be, for example,from about 0.25 mg to about 4 mg, and in certain preferred embodimentsabout 2 mg.

In certain embodiments, the topical formulation is used to treatADD/ADHD and/or Tourette's syndrome. In such embodiments, the topicalformulation comprises a therapeutically effective amount ofcaryophyllene and a therapeutically effective amount of phentermine. Thetherapeutically effective amount of phentermine may be, for example,from about 5 mg to about 40 mg, and in certain preferred embodimentsabout 10 mg.

In certain embodiments, the topical formulation is used to treat anxietyand panic attacks, or mood disorders. In such embodiments, the topicalformulation may comprise a therapeutically effective amount ofcaryophyllene and a therapeutically effective amount of anantidepressant (such as milnacipran or another serotonin-norepinephrinreuptake inhibitor (SNRI). The therapeutically effective amount ofmilnacipran may be, for example, from about 12.5 mg to about 100 mg, andin certain preferred embodiments about 25 mg.

In certain embodiments, the topical formulation is used to treatdiabetic peripheral neuropathy (DPN) and other peripheral neuropathicconditions. In such embodiments, the topical formulation may comprise atherapeutically effective amount of carylophyllene and a therapeuticallyeffective amount of 4-aminopyridine or a therapeutically activederivative thereof. The therapeutically effective amount of4-aminopyridine may be, for example, from about 5 mg to about 40 mg, andin certain preferred embodiments about 10 mg.

In certain embodiments, the topical formulation is used to treatspasticity and/or spasms. In such embodiments, the topical formulationmay comprise a therapeutically effective amount of caryophyllene and atherapeutically effective amount a dopamine agonist (e.g., apomorphine).The therapeutically effective amount of dopamine agonist may be, forexample, from about 0.25 mg to about 4 mg, and in certain preferredembodiments about 2 mg. One skilled in the art can readily determinetherapeutically equivalent doses of other dopamine agonists such asthose mentioned herein that may be useful in the present invention.

In certain embodiments, the topical formulation is used to greatmigraine and/or tension headache. In such embodiments, the topicalformulation may comprise a therapeutically effective amount ofcaryophyllene and a therapeutically effective amount of a dopamineagonist such as sumatriptan and (optionally) a skeletal muscle relaxant(e.g., tizanidine). The therapeutically effective amount of skeletalmuscle relaxant may be, for example, from about 0.25 mg to about 50 mg,and in certain preferred embodiments about 5 mg. One skilled in the artcan readily determine therapeutically equivalent doses of other skeletalmuscle relaxants such as those mentioned herein that may be useful inthe present invention.

Formulations

All currently approved therapies for the conditions described abovereach the central nervous system through the systemic circulation.Cerebral blood flow to brainstem structures is through the posteriorcirculation, via the vertebral and basilar arteries and their branches.In view of the undesirable side-effects associated with this form ofdrug delivery to the brain, it makes sense that targeted regionaldelivery to the brainstem is sought. Topical delivery of currently useddrugs compounded in an appropriate “dermal penetration enhancer” andapplied in cream/gel form or as a sustained-release patch at theposterior cervical region (back of the neck) at the hairline is such amethod. Lipoderm® is an example of an effective commercially availablecompounding medium. However, one skilled in the art will recognize thattopical carriers meeting the specific chemical requirements of anindividual drug can be formulated for maximum efficiency in topicaldelivery. Another example of an effective commercially availablecompounding medium is a liposomal base such as liposomal basecommercially available from LETCO Medical Decatur, Ala. In embodimentswhere the caryophyllene is incorporated into a topical foam, acommercially available lipophilic foam base solution may be used. Anexample of such a formulation is Espumil™, a lipophilic foam basesolution where the foam is generated by a foam-activating dispenser. Thedelivery features of Espumil™ assure simple application of lipophilicactive pharmaceutical ingredients (APIs) on difficult-to-treat areas,like hairy skin and the scalp, without dripping. This product is free offragrances, dyes, parabens, mineral oil, SLS and 1,4-dioxane and isgently preserved. Its Ingredients are purified water, alcohol,humectant, acidifying agent, emulsifier, foaming agent, and anantioxidant.

The formulations of the present invention are prepared such that thedrug(s) may be delivered acutely as single dose applications ascream/gel/ointment or as a sustained release topical patch, depending onthe condition treated and associated symptom complex in the individualpatient. The critical point, again, is in the location of theapplication: at the back of neck at the hair-line for access toposterior cervical afferents with free nerve endings under the surfaceof the skin. Through feedback connections with vagal and trigeminalafferent systems, this results in ultimate effect on brainstemstructures.

By virtue of the method of treatment described herein, the diseasestate/condition to be treated may be treated much faster and moreeffectively than such prior art modes of administration.

In certain embodiments of the present invention, the method of treatinga human patient comprises applying a topical formulation which comprisesa drug suitable for topical administration, which is useful for thetreatment of a disease state or condition treatable via the topicalbrainstem afferent stimulation (de-afferentation) drug therapy describedherein.

The methods of the present invention may also, if desired, involvepre-treatment of the skin with an enhancer to increase the permeabilityof the skin to the applied drug. The methods of the present inventionmay include pre-treatment or “prepping” of the skin area with asubstance that opens up the skin pores. Additionally, the methods of thepresent invention may include, if desired, pre-treatment or “prepping”of the skin with an alcohol swab or the like to rid the area of dirt,make-up, oil, and the like, prior to application of the drug.

In certain embodiments, the topical formulation of the present inventioncomprises a drug in an amount which is therapeutically effective whenadministered topically at the at the back of neck at the hair-line foraccess to posterior cervical afferents with free nerve endings under thesurface of the skin, but which provides a plasma concentration which issub-therapeutic if orally administered.

In certain embodiments, by applying the formulation of the presentinvention comprising a dose of drug at the back of neck at the hair-linefor access to posterior cervical afferents with free nerve endings underthe surface of the skin, it may be possible for the use of lower dosesof drug or faster relief of the headache than if applied to the trunk orlimbs of a human patient, and the lower plasma levels of drug whichresult from lower doses may thereby reduce unwanted side effects of thedrug.

The topical formulations of the present invention (e.g., ointment, gel,cream, or the like), must be suitable for topical administration of adrug, i.e., must contain pharmaceutically acceptable excipientscompatible with application to the skin tissue, and may optionallycontain a sufficient amount of an enhancer composition as describedhereinafter.

In certain embodiments, in addition to the drug (e.g., caryophyllene),the topical formulations and/or transdermal therapeutic systems of thepresent invention may include at least one adjuvant such as apenetration enhancer, anti-oxidant, stabilizer, carrier, or vehicle.Additionally or alternatively, the present invention may include theapplication of electric current (iontophoresis) for enhancing permeationof the drug(s).

Suitable penetration enhancers useful in the formulations of the presentinvention include but are not limited to isostearic acid, octanoic acid,oleic acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropylmyristate, butyl stearate, methyl laurate, diisopropyl adipate, glycerylmonolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether,polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol,diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethylethers, polyethylene oxide dimethyl ethers, dimethyl sulfoxide,glycerol, ethyl acetate, acetoacetic ester, N-alkylpyrrolidone, andterpenes.

In certain embodiments, the topical formulations comprising a drug in anointment, gel, cream or the like, will typically contain on the order ofabout 0.001 to about 80% by weight, preferably 0.01 wt. % to 50 wt. %drug (i.e., caryophyllene) plus optional additional drugs as describedherein), and about 0 wt. % to about 50.0 wt. %, preferably from about 1wt. % to about 30 wt. % of a permeation enhancer composition, with theremainder of the composition comprising a carrier or vehicle. In certainpreferred embodiments, the drug is included in a cream or gel orointment in a concentration of, e.g., 1 mg drug/ml of carrier (e.g.,Lipoderm). However, it is to be understood that one skilled in the artcan increase the amount of carrier or change the carrier and maintain orimprove efficacy of the topical formulation for TRNA therapy. In certainpreferred embodiments, the drug is applied as a unit dose at the back ofthe neck or at the BONATH in immediate release form (e.g., cream,ointment or gel) for acute treatment with a caryophyllene as would bebeneficial to a human patient. In such instances, it is preferred thatthe concentration of caryophyllene included in the unit dose is fromabout 3 mg to about 200 mg.

In certain embodiments, the topical formulations comprising acaryophyllene with or without additional drugs (collectively referred toherein as “drug(s)”) in an ointment, gel, cream or the like, willtypically contain on the order of about 0.001 to about 80% by weight,preferably 0.01 wt. % to 50 wt. % drug(s) or from about 0.5% to about 5%drug(s); and about 0 wt. % to about 50.0 wt. %, preferably from about 1wt. % to about 30 wt. % of a permeation enhancer composition, with theremainder of the composition comprising a carrier or vehicle. In certainpreferred embodiments, the drug comprises caryophyllene and is includedin a cream or gel or ointment in a concentration of, e.g., 1 mg drug/mlof carrier (e.g., Lipoderm). However, it is to be understood that oneskilled in the art can increase the amount of carrier or change thecarrier and maintain or improve efficacy of the topical formulation forTRNA therapy.

Suitable (optional) permeation enhancers may also be included in theformulations. Such enhancers include, but are not limited to,dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA),decylmethylsulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML),propylene glycol (PG), PGML, glycerol monolaurate (GML), lecithin, the1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAxone® from Whitby Research Incorporated, Richmond, Va.), alcohols, andthe like. The permeation enhancer may also be a vegetable oil asdescribed in U.S. Pat. No. 5,229,130 to Sharma. Such oils include, forexample, safflower oil, cotton seed oil and corn oil.

Additional optional enhancers for use in conjunction with the presentinvention are lipophilic compounds having the formula [RCOO]n R′,wherein n is 1 or 2 and R is C1-C 16 alkyl optionally substituted with 1or 2 hydroxyl groups, and R′ is hydrogen or C1-C16 alkyl optionallysubstituted with 1 or 2 hydroxyl groups. Within this group, a firstsubset of compounds are represented by the formula [CH3 (CH 2)m COO]n R′in which m is an integer in the range of 8 to 16, n is 1 or 2, and R′ isa lower alkyl (C1-C3) residue that is either unsubstituted orsubstituted with one or two hydroxyl groups. Preferred enhancers withinthis group include an ester which is a lower alkyl (C1-C3) laurate(i.e., m is 10 and n is 1) such as “PGML”. It will be appreciated bythose skilled in the art that the commercially available material soldas “PGML” is typically although not necessarily a mixture of propyleneglycol monolaurate itself, propylene glycol dilaurate, and eitherpropylene glycol, methyl laurate, or both. Thus, the terms “PGML” or“propylene glycol monolaurate” as used herein are intended to encompassboth the pure compound as well as the mixture that is typically obtainedcommercially. Also within this group is a second subset of compounds,namely, esters of fatty alcohols represented by the formula CH3(CH2)m-O—CO—CHR1 R2, in which R1 and R2 are independently hydrogen,hydroxyl, or lower alkyl (C1-C3), and m is as above. Particularlypreferred enhancers within this group are lauryl lactate and myristyllactate. In addition, a third subset of compounds within this group areanalogous fatty acids, i.e., acids having the structural formula CH3(CH2)m COOH where m is as above. A particularly preferred acid is lauricacid.

Other optional enhancer compositions are wherein a lipophilic compoundas just described, particularly PGML is combined with a hydrophiliccompound, such as a C2-C6 alkanediol. One preferred hydrophilic enhancerwithin this group is 1,3-butanediol. Such enhancer compositions aredescribed in detail in PCT Publication No. WO 95/05137, published Feb.23, 1995, herein incorporated by reference. Another hydrophilic enhancerthat may be included in these compositions is an ether selected from thegroup consisting of diethylene glycol monoethyl ether (Transcutol) anddiethylene glycol monomethyl ether. Such enhancer compositions aredescribed in detail in U.S. Pat. Nos. 5,053,227 and 5,059,426 to Chianget al., the disclosures of which are herein incorporated by reference.

Other optional enhancer compositions may include mixture or combinationsof any of the aforementioned enhancers, and the like.

One preferred topical formulation comprises the caryophyllene in oil,together with a suitable amount of a penetration enhancer, dimethylsulfoxide and a base. For example, such a formulation may include thecaryophyllene oil, and about 3 ml dimethyl sulfoxide in 30 g of base.

In certain preferred embodiments, the caryophyllene can be incorporatedat a concentration of, e.g., from about 0.5% to about 5% of the topicalformulation, preferably from about 1.5% to about 4%, and most preferablyfrom about 2% to about 3% in certain embodiments. The unit dose of sucha topical formulation would be, e.g., from about 0.5 g to about 1 gapplied topically on the back of the neck of the human patient.

U.S. Patent Publication No. 20080112895, hereby incorporated byreference, describes a room temperature stable aqueous cannabinoidformulation comprising an effective amount of a cannabinoid in asemi-aqueous solution buffered to a pH of about 5-1, the solutioncomprising water and an effective amount of an organic cosolvent tomaintain the physical stability of the formulation, which may beincorporated into a pharmaceutically acceptable carrier.

In certain embodiments the topical formulation may include at least onewater-insoluble, pharmacologically approved, alkyl cellulose orhydroxyalkyl cellulose, and the like. Alkyl cellulose or hydroxyalkylcellulose polymers for use in this invention include ethyl cellulose,propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropylcellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose,alone or in combination. In addition, a plasticizer or a cross linkingagent may be used to modify the polymer's characteristics. For example,esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asacid oleic and myristyl may be used in combination with the cellulosederivative.

In certain embodiments, the topical formulation may further includehydrocarbons such as liquid paraffin, qualene, solid paraffin,microcrystalline wax, etc.; higher aliphatic alcohols such as cetylalcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.;esters of higher fatty acids with higher alcohols such as beeswax, etc.;esters of higher fatty acids with lower alcohols such as isopropylm.yristate, isopropyl palmitate, etc.; vegetable oils, modifiedvegetable oils, hydrous lanolin and its derivative, squalene, 47qualene;higher fatty acids such as palmitic acid, stearic acid, etc. and thelike.

In certain embodiments, the topical formulation may further includeemulsifiers and dispersing agents which include, for example, anionic,cationic and nonionic surfactants. Nonionic surfactants are preferredbecause of their low levels of irritation to skin. Typical of nonionicsurfactants are fatty acid monoglycerides such as glyceryl monostearate,etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.;sucrose fatty acid esters; polyoxyethylene fatty acid esters such aspolyoxyethylene stearate, etc.; and polyoxyethylene higher alcoholethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,etc.

In certain preferred embodiments, the topical TRNA formulation isaqueous-based.

In certain embodiments of the present invention, the topical formulationmay include a gelling agent such as methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl-cellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and thelike. Examples of pharmaceutical compositions which rely upon an aqueousgel composition as a vehicle for the application of a drug are U.S. Pat.Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780, thedisclosures of which are herein incorporated by reference.

The topical formulation may further ide one or more preservatives,stabilizers, or anti-oxidants.

Examples of preservatives that may be used in a formulation according tothe present invention include, but are not limited to, bacteriostaticcompounds and other preservatives suitable for topical administrationincluding various alcohols, sorbic acid and salts and derivativesthereof, ethylenediamine, monothioglycerol, and thimerosal.

Examples of stabilizers that may be present in a formulation accordingto the present invention include pH buffers suitable for topicaladministration, compleximg agents, chelating agents and the like.

Examples of anti-oxidants that may be used in a formulation according tothe present invention include ascorbic acid and its derivatives, e.g.,ascorbyl palmitate, as well as butylated hydroxyanisole, butylatedhydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.

Other adjuvants that may be included in the drug formulation includecarriers, tackifiers, pigments, dyes, and other additives that do notadversely affect the mechanical or adhesive properties of theformulation.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal drug administration, and include any suchmaterials known in the art, e.g., any liquid, gel, emulsion, solvent,liquid diluent, solubilizer, or the like, which is nontoxic and whichdoes not interact with other components of the composition in adeleterious manner. The term “carrier” or “vehicle” as used herein mayalso refer to stabilizers, crystallization inhibitors, dispersing agentsor other types of additives useful for facilitating transdermal drugdelivery. It will be appreciated that compounds classified as “vehicles”or “carriers” may sometimes act as permeation enhancers, and vice versa,and, accordingly, these two classes of chemical compounds orcompositions may sometimes overlap.

Carrier materials suitable for use in the instant compositions includethose well-known for use in the cosmetic and medical arts as bases forointments, lotions, salves, aerosols, suppositories and the like.Suitable carriers include, for example, water, liquid alcohols, liquidglycols, liquid polyalkylene glycols, liquid esters, liquid amides,liquid protein hydrolysates, liquid alkylated protein hydrolysates,liquid lanolin and lanolin derivatives, and like materials commonlyemployed in cosmetic and medicinal compositions. Other suitable carriersherein include for example alcohols, including both monohydric andpolyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.In certain preferred embodiments, the carrier is an aqueous basedcannabidiol cream is produced using Lipoderm® as the carrier.Lipoderm®/LIP is a whitish cream with no smell, commercially marketedcompounding agent (from PCCA, Pharmaceutical Compounding Centers ofAmerica) having the following ingredients: Ethoxydiglycol, Water (Aqua),Glycerin, C₁₂₋₁₅Alkyl Benzoate, Glyceryl Stearate, Dimethicone, CetearylAlcohol, Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, MagnesiumAluminum Silicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), TocopherolAcetate (Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond)Kernel Oil, Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare(Wheat) Germ Oil, Retinyl Palmitate (Vitamin A Palmitate), AscorbylPalmitate (Vitamin C Palmitate), Pro-Lipo Multi-emulsion LiposomicSystem, Tetrasodium EDTA, Phenoxyethanol, and SodiumHydroxymethylglycinate.

In certain embodiments of the invention, part or all of the dose ofcaryophyllene may be encapsulated within liposomes as described in U.S.Patent Publication No. 2015/0302148, hereby incorporated by reference.For example, fast-acting liposomal and micelle formulations ofcaryophyllene may be prepared by (a) dissolving caryophyllene in ethanolto obtain an ethanol caryophyllene solution; (b) adding a phospholipidto the ethanol caryophyllene solution to obtain an ethanol-phospholipidcannabinoid solution; (c) injecting the ethanol-phospholipidcaryophyllene solution into distilled water to obtain a liposomalcaryophyllene suspension; and (d) removing the ethanol from theliposomal caryophyllene suspension, thereby producing a stable liposomalsuspension. In certain embodiments, the method further comprises thestep of adding sodium alginate to the liposomal suspension to obtain analginate liposomal caryophyllene suspension that has a final alginateconcentration of 2% w/v, followed by the addition of calcium chloride tothe alginate liposomal cannabinoid suspension to obtain a calciumalginate-encapsulated liposomal caryophyllene suspension. Thissuspension is then cold-pressed and air-dried to remove the water so asto obtain a dry caryophyllene powder. The dry caryophyllene powder canbe re-suspended in citrate buffer to obtain an aqueous caryophyllenesolution. The amount of caryophyllene in the aqueous solution may be,e.g., greater than 40%.

In certain preferred embodiments of the present invention where it isdesired that the drug is administered chronically, the formulations ofthe present invention may be formulated as a transdermal delivery system(also referred to herein as a transdermal therapeutic system) such as atransdermal patch, a transdermal plaster, a transdermal disc,iontophoretic transdermal device, or the like. Such formulations arerecognized by those skilled in the art as providing a release of drugand absorption into the skin of the patient in a sustained manner overan extended period of time (e.g., 1-7 days). In such embodiments of thepresent invention, the transdermal delivery system comprises, e.g.,caryophyllene with or without an additional therapeutically effectiveactive agent(s) (drug) as described herein contained in a reservoir or amatrix, and an adhesive which allows the transdermal patch to adhere tothe skin, allowing the passage of the active agent from the transdermalpatch through the skin of the patient. In preferred embodiments, thetransdermal patch is applied topically at the back of the neck so as toachieve topical regional neuro-affective therapy (“TRNA THERAPY”) asdescribed herein. In embodiments in which the drug is contained in atransdermal patch, it is contemplated that the drug will be absorbedmore slowly and the transdermal patch will provide a sustained releaseand prolonged therapeutic effect, as compared, e.g., to a cream orointment intended to provide an immediate release of the drug and rapidonset of the TRNA therapy. In such embodiments, the dose ofcaryophyllene may be that which is sufficient to provide atherapeutically effective dose to the back of the neck (e.g.,non-systemic dose) over the course of e.g., from about 1, 2, 3, 4, 5, 6or 7 days. In certain embodiments, the dose of caryophyllene containedin the transdermal delivery system is from about 120 mg to about 1000mg. As there are only a finite number of receptors on the skin, oncethese receptors are bound, the rest of the active drug is contained inthe (e.g., topical) preparation is superfluous. Therefore, there is nopossibility of “over-dosing,” only of extra drug of potentiallyirritating the skin surface. Accordingly, in preferred embodiments, themethods and formulations of the present invention provide reduced sideeffects as compared to a systemic administration of the same drug.

In certain embodiments, the transdermal delivery devices, as well asother transdermal delivery systems in accordance with the invention canbe made in the form of an article such as a tape, a patch, a sheet, adressing or any other form known to those skilled in the art. Generallythe device will be in the form of a patch of a size suitable to delivera unit dose of serotonin agonist through the skin. The drug may beintroduced into a transdermal therapeutic system in different forms(solid, in solution, in dispersion); it may also be microencapsulated.

In certain embodiments the present invention provides a transdermaltherapeutic system comprising caryophyllene in an amount that wouldprovide sub-therapeutic plasma levels if administered orally, but istherapeutically effective when administered via transdermal delivery atthe back of the neck.

A transdermal delivery system for use in accordance with the presentinvention can also be constructed with an enhancer composition and otheringredients described hereinabove with respect to the topicalformulation. Preferably, the transdermal delivery system is formulatedfor the prolonged delivery of caryophyllene. The targeted skin flux fordelivery of the caryophyllene can be achieved by adjusting vehiclecomposition and vehicle loading, as well as by adjusting the surfacearea through which the compositions are administered to skin.

In certain preferred embodiments, the transdermal delivery system (e.g.,patch) is formulated to deliver from about 1 mg to about 200 mgcaryophyllene per each 24 hours through the skin of the patient. Inembodiments in which the transdermal delivery system is intended to beapplied to the skin at the back of the neck for multiple days, thetransdermal delivery system (e.g., patch) is formulated to provide aflux rate over the useful life of the system such that a similar amount(e.g., mean dose) is delivered on a daily basis until the system isremoved and replaced with a fresh system.

The transdermal delivery system used in the present invention may beprepared, for example, in accordance with U.S. Pat. Nos. 5,069,909;4,806,341; 5,026,556; 4,588,580; 5,016,652; 3,598,122; 4,144,317;4,201,211; 4,262,003; and 4,379,454; all of which are incorporatedherein by reference.

Additionally, the transdermal delivery system used in the presentinvention may be in accordance with U.S. Pat. No. 6,689,379, herebyincorporated by reference, which system is a matrix or reservoir systemwhich comprises at least one pharmaceutical active agent and apressure-sensitive adhesive comprising a polyacrylate polymer, whereinsaid polyacrylate polymer has a polyacrylate backbone containing monomerunits selected from the group consisting of acrylic acid, methacrylicacid and ester derivatives of acrylic or methacrylic acid, and saidmonomer units comprise at least 50% (w/vv) relative to a mean polymermass of said polyacrylate polymer, a total amount of monomers selectedfrom the group consisting of non-esterified acrylic acid andnon-esterified methacrylic acid is 0.5 to 10.0% (w/w) relative to themean polymer mass of said polyacrylate polymer, and the carboxyl groupsof said non-esterified acrylic and methacrylic acid monomers are presentstoichiometrically at 5 to 100% in the form of alkali salts oralkaline-earth salts, said salts being reaction products of aneutralization reaction of an alcoholic solution of an alkalinehydroxide or an alkaline-earth hydroxide with said acrylate polymer(s),or of a neutralization reaction of an alkali alcoholate or analkaline-earth alcoholate with said acrylate polymer(s).

In certain embodiments, the dosage form can be a transdermal patchcomprising a laminated composite for administering the drug (e.g.,cannabinoid drug(s)) to an individual transdermally comprising: (a) apolymer backing layer that is substantially impermeable tocaryophyllene; and (b) a reservoir layer comprising a water-baseacrylate pressure-sensitive adhesive, 1 to 12% by weight serotoninagonist and 2 to 25% by weight of a permeation enhancer comprisingpropylene glycol monolaurate in combination with capric acid or oleicacid, wherein the skin contact area of the composite is 10 to 100 cm2.

The dosage form can be a transdermal patch comprising (a) a polarsolvent material selected from the group consisting of C3-C4 dials,C3-C6 triols, and mixtures thereof; and (b) a polar lipid materialselected from the group consisting of fatty alcohol esters, fatty acidesters, and mixtures thereof; wherein said polar solvent material andsaid polar lipid material are present in a weight ratio of solventmaterial:lipid. material of from about 60:40 to about 99:1.

In certain embodiments, the dosage form also comprises a transdermalplaster comprising: (1) a film layer which comprises a polyester film of0.5 to 4.9 microns thickness, 8 to 85 g/mm strength, respectively in thetwo directions intersecting substantially at right angles, 30 to 150%elongation, in the two directions intersecting substantially at rightangles and an elongation ratio of A to B of 1.0 to 5.0, wherein A and Brepresent data in two directions intersecting at right angles, and A isgreater than B, and wherein said polyester film comprises 0.01 to 1.0%by weight, based on the total weight of said polyester film, of solidfine particles in which (a) the average particle size is 0.001 to 3.0microns, and (b) the average particle size is substantially not morethan 1.5 times the thickness of said polyester film; and (2) an adhesivelayer (a) which is composed of an adhesive containing said serotoninagonist and further wherein said adhesive layer (a) is laminated on saidfilm layer over the surface in a 2 to 60 microns thickness.

In certain embodiments, the dosage form can be a transdermal disccomprising: (a) a backing layer which is substantially impervious tocaryophyllene; and (b) a polymer matrix disc layer which is adhered tosaid backing layer and which has microdispersed therein said serotoninagonist, said polymer being bioacceptable and permitting said serotoninagonist to be transmitted for transdermal absorption, caryophyllenebeing stable in said polymer matrix.

In certain embodiments, the topical formulation or transdermaltherapeutic system may further comprise another active ingredient incombination with the first drug (e.g., as previously described herein).

The present invention is contemplated to encompass all transdermalformulations, e.g., the technologies described above, with the inclusionof caryophyllene, such that the administration of a drug useful fortreatment of disease state or condition in humans via topical brainstemafferent stimulation (de-afferentation) therapy via topicaladministration. Therefore, modifications of the invention via, e.g., thechoice and/or amount of drug are considered to be obvious variations ofthis disclosure and within the scope of the appended claims.

The present invention also contemplates the administration of thecannabinoid drug(s) directly below the skin to affect direct brainstemafferent stimulation to the free nerve endings under the epidermis. Suchadministration may be effected as an injection (e.g., subcutaneousinjection) or implantation of the drug in immediate release or sustainedrelease form. It will be appreciated by those skilled in the art thatproviding the drug in sustained release form and administering it in asuitable form below the skin may provide benefits, including lessfrequent administration (e.g., in chronic therapy).

In certain embodiments of the invention, caryophyllene can be formulatedfor controlled or sustained delivery at the back of the neck viaincorporation into a biocompatible and implantable polymer which can bein the form of microparticles or an implantable insert, or a liquid thatforms a gel or colloid or a semi-solid after injection (therebyencapsulating the drug and allowing it to be released in a prolonged andcontrolled manner at the desired site). For chronic conditions (e.g.,Parkinson's) or desired prolonged effect, it is contemplated that a drugdepot or reservoir may be created under the skin at the back of theneck, which then provides a sustained release of the drug in proximityto the desired nerve endings and which may be replenished or replaced atthe end of the dosing interval. It is contemplated that suchadministrations of the drug may provide a prolonged therapeutic effectfor at least about 3 days, preferably at least about 7 days, or longer.Such formulations may be administered in certain embodiments as, forexample, a subcutaneous depot.

Implants are placed subcutaneously by making an incision in the skin andforcing the implants between the skin and the muscle. At the end oftheir use, if not dissolved, these implants are surgically removed. U.S.Pat. No. 4,244,949, hereby incorporated by reference, describes animplant which has an outer matrix of an inert plastic such aspolytetrafluoroethylene resin. Examples of this type of implantabletherapeutic system are Progestasert IUD and Ocusert system. It iscontemplated that such systems can be appropriately modified by oneskilled in the art for use in conjunction. with the present invention. Acommercially available product, Norplant®, which is an implant having acore containing levonorgestrel as the active substance, and where thecore it surrounded by a membrane of a silicone elastomer ofpoly(dimethylsiloxane) (PDMS). Another preparation of this kind isJadelle®, in which the core is a poly(dimethylsiloxane) based matrixwith levonorgestrel dispersed therein. The membrane is an elastomer madefrom PDMS and silica filler, which, besides giving necessary strengthproperties to the membrane, also retards the permeation of the activeagent through the membrane. U.S. Pat. No. 3,854,480, hereby incorporatedby reference, describes a drug delivery device, e.g. an implant, forreleasing a drug at a controlled rate for a prolonged period of time.The device has a core of a matrix in which the drug is dispersed. Thecore is surrounded by a membrane that is insoluble in body fluids. Thecore matrix as well as the membrane are permeable to the drug bydiffusion. The materials of the core and the membrane are chosen so thatthe drug diffuses through the membrane at a lesser rate than through thecore matrix. Thus, the membrane controls the release rate of the drug.As a suitable polymer for the core matrix is mentionedpoly(dimethylsiloxane) (PDMS), and as suitable polymers for the membraneare mentioned polyethylene and a copolymer of ethylene and vinyl acetate(EVA). It is contemplated that the above systems may be adapted by oneskilled in the art to deliver caryophyllene in accordance with thepresent invention.

One device which may be adapted by one skilled in the art for use in thepresent invention is described in U.S. Pat. No. 5,968,542 (Tipton),hereby incorporated by reference, which describes a high viscosityliquid controlled delivery system as a medical or surgical device isprovided that includes: (i) a non-polymeric, non-water soluble liquidcarrier material (HVLCM) of viscosity of at least 5,000 Cp at 37° C.that does not crystallize neat under ambient or physiologicalconditions; and, optionally, (ii) substance to be delivered.

The pharmaceutical compositions suitable for injectable use inaccordance with this invention include sterile aqueous solutions ordispersions and sterile powders or lyopholysates for the extemporaneouspreparation of sterile injectable solutions or dispersions. The dosageforms must be sterile and it must be stable under the conditions ofmanufacture and storage. The carrier for injectable formulations istypically water but can also include ethanol, a polyol (for example,glycerol, propylene glycol and liquid polyethylene glycol), mixturesthereof, and vegetable oil.

Injectable formulations used in the present invention can also beformulated as injectable prolonged release formulations in which theactive compound is combined with one or more natural or syntheticbiodegradable or biodispersible polymers such as carbohydrates,including starches, gums and etherified or esterified cellulosicderivatives, polyethers, polyesters, polyvinyl alcohols, gelatins, oralginates. Such dosage formulations can be prepared for example in theform of microsphere suspensions, gels, or shaped polymer matrix implantsthat are well-known in the art for their function as “depot-type” drugdelivery systems that provide prolonged release of the biologicallyactive components. Such compositions can be prepared usingart-recognized formulation techniques and designed for any of a widevariety of drug release profiles.

One example of a useful formulation which may be used in the methods ofthe present invention for providing a prolonged duration of action isdescribed in U.S. Pat. No. 7,332,503 (Wikstrom, et al.), herebyincorporated by reference. Therein, apomorphine derivatives and thephysiologically acceptable salts thereof as well as formulations thereofare described which provide a prolonged duration of action. Theapomorphine pro-drugs can be suspended (as a neat oil or as crystals, ordissolved in a suitable and pharmaceutically acceptable solvent (e.g.water, ethanol, DMSO, i-PrOH or benzylbenzoate) in a pharmaceuticallyacceptable depot oil (e.g. viscoleo, sesame oil or olive oil) andinjected subcutaneously or intramuscularly with a syringe or a “peninjector”. Alternatively, these drugs may, in a suitable composition andwith a suitable vehicle (penetration enhancer), be applied to a patchfor transdermal administration. The composition could include also alocal anesthetic (e.g. lidocaine) to avoid injection pain, in particularat intramuscular injections. In one embodiment, the composition is inthe form of a patch or an ointment for transdermal administration. Thepatch or ointment preferably also comprises stabilizers, solubilizersand permeation activators to facilitate the passage of the activeprinciple through the skin. In another preferred embodiment, thecomposition is in the form of a depot preparation for subcutaneous orintramuscular administration comprising caryophyllene dissolved orsuspended in an oil. In certain embodiments, in addition to theapomorphine derivative, the formulation further contains a localanesthetic. The formulations described in the '503 patent can bemodified as understood by one skilled in the art to contain other activedrugs as described herein for use at the hack of the neck, e.g., BONATH.

An injectable depot formulation is a dosage form, which is generallyintended to have a therapeutic activity for 2 to 4 weeks afteradministration (e.g. in sesame oil). In order to maintain effective drugplasma levels the dosage form should release the drug at a more or lessconstant rate during the desired dosing interval. The difference betweensuch prior art depots and depots used in the present invention is thatthe in accordance with the present invention, the drug is not needed tobe absorbed into the systemic circulation.

A suitable form of depot preparation is the subcutaneous orintramuscular administration of an oil solution and/or oil suspension ofa lipophilic drug. This gives a slow transport over the oil-biofluidinterface and a slow dissolution in the biophase. Thus, when the drug isdissolved in a polar solvent (e.g. oils), which is non-miscible with theaqueous biological fluids, the drug has to be transported over theoil/water interface. When the oil/water partition coefficient is high,the transport will be slow. For very lipophilic drugs, the release fromthe oil phase may last for up to several weeks. The use of depotpreparations such as those described herein may be used to deliver thedrugs described herein at the back of the neck, e.g., BONATH.

The maximum volume of an oil solution/suspension to be injectedintramuscularly or subcutaneously is 2-4 MI. This is feasible for thepreparations of the cannabinoid drug formulations of the presentinvention. For example, caryophyllene may be dissolved or dispersed in 1MI of an oil (sesame oil, Viscoleo or another approved oil) and themixture gently heated (max 50° C.) shaken in a test tube shaker andultrasonicated for a short time (minutes) until the mixture becomes ahomogeneous solution or suspension. If necessary, caryophyllene mayfirst be dissolved in 50-300 μl DMSO, water, t-BuOH, PEG,benzylbenzoate, or another suitable and approved solvent or mixturesthereof, before adding the oil to a total volume of 1 MI.

Another example of a polymeric drug delivery system which may be adaptedfor use in the present invention by one skilled in the art is describedin U.S. Pat. No. 5,601,835 (Sabel, et al.), hereby incorporated byreference, which describes a polymeric drug delivery system for deliveryof any substance to the central nervous system. The delivery system ispreferably implanted in the central nervous system for delivery of thedrug directly to the central nervous system. These implantable devicescan be used, for example, to achieve continuous delivery of dopamine,which cannot pass the blood brain barrier, directly into the brain foran extended time period. The implantable devices display controlled,“zero-order” release kinetics, a life time of a minimum of several weeksor months even when the devices contain water soluble, low molecularweight compounds, biocompatibility, and relative non-invasiveness. Thepolymeric devices are said to be applicable in the treatment of avariety of central nervous system disorders including Parkinson'sdisease, Alzheimer's dementia, Huntington's disease, epilepsy, trauma,stroke, depression and other types of neurological and psychiatricillnesses, and one skilled in the art can adapt that drug deliverysystem for delivering the drugs contemplated herein at the hack of theneck, e.g., BONATH.

Yet another example of a system that may be adapted for use in thepresent invention is described in U.S. Pat. No. 5,601,835 (Sabel, etal.), hereby incorporated by reference, wherein an active compound isencapsulated within a polymer to form a polymeric device, the deviceformed of a biocompatible polymer that is plastically deformableselected from the group consisting of ethylene vinyl acetate,polyurethanes, polystyrenes, polyamide, polyacrylamide, and combinationsthereof having a non-porous polymer coating thereon with one or moreopenings, with limited water sorptivity and slight permeability to thepassage of small, aqueous-soluble molecules, wherein said compound islinearly released (e.g., zero order release) from said polymeric deviceover a sustained period of time of at least 65 days at a predeterminedlevel and rate when implanted in a patient at a specific site within thecentral nervous system where the compound is released directly into thecentral nervous system and the device remains essentially intactthroughout the release period. The delivery device is a two-phase systemthat is manufactured using standard techniques such as blending, mixingor the equivalent thereof, following selection of the biologicallyactive material to be delivered and an appropriate polymer for formationof the matrix. The general method of solvent casting as disclosed bySiegel and Langer, “Controlled release of polypeptides and othermacromolecules”, Pharmaceutical Research 1, 2-10 (1984), is modified sothat drug is dispersed within the devices to create channels and poresto the surface for release of the drug at the desired rate. Whereappropriate, a coating impermeable to the drug is placed over a portionof the drug containing polymer matrix to further regulate the rate ofrelease. One skilled in the art can adapt that drug delivery system fordelivering the drugs contemplated herein at the back of the neck, e.g.,BONATH.

Yet another formulation which may used to deliver the drug as set forthin the present invention at the back of the neck, e.g., BONATH, isdescribed in U.S. Pat. No. 7,314,636 (Caseres et al.), herebyincorporated by reference, which describes injectable implantscomprising glycolic acid and bio-compatible/bio-absorbable polymericparticles containing polymer of lactic acid. The particles are smallenough to be injected through a needle but large enough to avoidengulfment by macrophages. The injectables of this invention may be in apre-activated solid form or an activated form (e.g., injectablesuspension or emulsion).

It is further contemplated that the system described in U.S. Pat. No.6,586,006 (Roser, et al.), hereby incorporated by reference, can beadapted by one skilled in the art for use in the present invention fordelivery of drugs at the back of the neck, e.g., BONATH. Therein aredescribed delivery systems suitable for delivery of bioactive materialsto subcutaneous and intradermal, intramuscular, intravenous tissue, thedelivery system being sized and shaped for penetrating the epidermis.The delivery systems comprise a vitreous vehicle loaded with the guestsubstance and capable of releasing the guest substance in situ atvarious controlled rates. Subdermal implantable therapeutic systems havealso been formulated for slow release of certain pharmaceutical agentsfor extended periods of time such as months or years. A well-knownexample is Norplant® for delivery of steroid hormones.

In membrane permeation-type controlled drug delivery, the drug isencapsulated within a compartment that is enclosed by a rate-limitingpolymeric membrane. The drug reservoir may contain either drug particlesor a dispersion (or solution) of solid drug in a liquid or a matrix typedispersing medium. The polymeric membrane may be fabricated from ahomogeneous or a heterogeneous nonporous polymeric material or amicroporous or semipermeable membrane. The encapsulation of the drugreservoir inside the polymeric membrane may be accomplished by molding,encapsulation, microencapsulation, or other techniques. The implantsrelease drugs by dissolution of the drug in the inner core and slowdiffusion across the outer matrix. The drug release from this type ofimplantable therapeutic system should be relatively constant and islargely dependent on the dissolution rate of the drug in the polymericmembrane or the diffusion rate across or a microporous or semipermeablemembrane. The inner core may substantially dissolve over time; however,in devices currently in use, the outer matrix does not dissolve.

Other implantable therapeutic systems involve matrix diffusion-typecontrolled drug delivery. The drug reservoir is formed by thehomogeneous dispersion of drug particles throughout a lipophilic orhydrophilic polymer matrix. The dispersion of drug particles in thepolymer matrix may be accomplished by blending the drug with a viscousliquid polymer or a semisolid polymer at room temperature, followed bycross-linking of the polymer, or by mixing the drug particles with amelted polymer at an elevated temperature. It can also be fabricated bydissolving the drug particles and/or the polymer in an organic solventfollowed by mixing and evaporation of the solvent in a mold at anelevated temperature or under vacuum. The rate of drug release from thistype of delivery device is not constant. Examples of this type ofimplantable therapeutic system are the contraceptive vaginal ring andCompudose implant. PCT/GB 90/00497 describes slow release glassy systemsfor formation of implantable devices. The described implants arebioabsorbable and need not be surgically removed. One skilled in the artcan adapt these drug delivery systems for delivering the drugscontemplated herein at the back of the neck, e.g., BONATH.

In microreservoir dissolution-controlled drug delivery, the drugreservoir, which is a suspension of drug particles in an aqueoussolution of a water-miscible polymer, forms a homogeneous dispersion ofa multitude of discrete, unleachable, microscopic drug reservoirs in apolymer matrix. The microdispersion may he generated by using ahigh-energy-dispersing technique. Release of the drug from this type ofdrug delivery device follows either an interfacial partition or a matrixdiffusion-controlled process. An example of this type of drug deliverydevice is the Syncro-Mate-C Implant.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 6,576,263(Truong, et al.), hereby incorporated by reference, which describes apreformed object for delivering an active agent for a subject, thepreformed object including cross-linked protein, and methods of makingand using.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 6,287,588(Shih, et al.), hereby incorporated by reference, which describes acomposition and method for releasing a bio-active agent or a drug withina biological environment in a controlled manner. The composition is adual phase polymeric agent-delivery composition comprising a continuousbiocompatible gel phase, a discontinuous particulate phase comprisingdefined microparticles and an agent to be delivered. A microparticlecontaining a bio-active agent is releasably entrained within abiocompatible polymeric gel matrix. The bio-active agent release may becontained in the microparticle phase alone or in both the microparticlesand the gel matrix. The release of the agent is prolonged over a periodof time, and the delivery may be modulated and/or controlled. Inaddition, a second agent may be loaded in some of the microparticlesand/or the gel matrix.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 7,364,568(Angel, et al.), hereby incorporated by reference, which describes atransdermal transport device includes a reservoir for holding aformulation of an active principle, and a needle with a bore extendingalong the length of the needle from a first end of the needle to asecond end of the needle. The second end is substantially aligned to aplane parallel to a body surface of a biological body when the device isplaced on the body surface. The device also includes an actuator whichpumps the formulation through the bore of the needle between a targetarea of the body and the reservoir.

In yet other embodiments of the invention, the cannabinoid drug(s) isinfused into the patient at the back of the neck using technology knownto be useful for infusing other drugs, such as an insulin pump. One suchsystem, U.S. Pat. No. 7,354,420 (Steil, et al.), hereby incorporated byreference, describes a closed loop infusion system controls the ratethat fluid is infused into the body of a user. The closed loop infusionsystem includes a sensor system, a controller, and a delivery system.The sensor system includes a sensor for monitoring a condition of theuser. The sensor produces a sensor signal, which is representative ofthe condition of the user. The sensor signal is used to generate acontroller input. The controller uses the controller input to generatecommands to operate the delivery system. The delivery system infuses aliquid into the user at a rate dictated by the commands from thecontroller. Preferably, the sensor system monitors the glucoseconcentration in the body of the user, and the liquid infused by thedelivery system into the body of the user includes insulin.

The present invention is contemplated to encompass all implantable orinjectable formulations, e.g., the technologies described above, withthe inclusion of a drug(s) (e.g., cannabinoid drug(s)(s)), such that theadministration of a drug useful for treatment of disease state orcondition in humans via topical brainstem afferent stimulation(de-afferentation) therapy. Therefore, modifications of the inventionvia, e.g., the choice and/or amount of drug are considered to be obviousvariations of this disclosure and within the scope of the appendedclaims.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction on the generality of the invention specifiedabove.

Example 1 Topical Formulation

An aqueous based caryophyllene cream is produced using Lipoderm® as thecarrier. Lipoderm®/LIP is a commercially marketed compounding agent(from PCCA, Pharmaceutical Compounding Centers of America) having thefollowing ingredients: Ethoxydiglycol, Water (Aqua), Glycerin,C₁₂₋₁₅Alkyl Benzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol,Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, Magnesium AluminumSilicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate(Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil,Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil,Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin CPalmitate), Pro-Lipo Multi-emulsion Liposomic System, Tetrasodium EDTA,Phenoxyethanol, and Sodium Hydroxymethylglycinate. The concentration is30 mg of caryophyllene in 1 g of Lipoderm. Lipoderm is a whitish creamwith no smell.

Example 2

A 60 g topical formulation of caryophyllene is prepared by incorporating1.8 g caryophyllene, 20 g Pluronic 20%, 40 g Carbomer hydroalcoholic geland 1 ml ethyl alcohol to obtain a caryophyllene topical formulationhaving a 3% concentration of caryophyllene.

Example 3

A topical formulation is prepared by incorporating 1.8 g caryophyllene,3 ml glycerine and enough liposomal base (commercially available fromLETCO Medical Decatur, Ala.) for total quantity of 60 grams. Thecaryophyllene is present in the formulation in a 3% concentration, andmay be administered topically in a 1 g amount. After initialapplication, the topical caryophyllene formulation can be applied to theback of the neck of the human patient once a day, twice a day, threetimes a day, or four times a day depending on the condition to betreated and its severity.

Example 4

A topical foam formulation of caryophyllene is prepared utilizing 1.8 gcaryophyllene, and qs to 100 ml with Espumil™ (a lipophilic foam basesolution where the foam is generated by a foam-activating dispenser).

Example 5

The following patients were treated with a topical caryophylleneformulation (referred to in Table 1 as “Cari-Derm”, which is a topical3% caryophyllene formulation) administered on the back of the neck onhuman patients, as more specifically described below in Table 1. The 3%Cari-Derm formulation contained approximately 30 mg of caryophyllene ina unit dose (1 gram).

TABLE 1 Demographics Clinical Condition & Current Rx Clinical Resultsand Observations 1. 50 ADD and Anxiety Disorder. Had been on Aftertopical 30 mg Cari- y/o female Vyvanse ® (lisdexanfetamine dimesylate),Derm, anxiety reduced from Strattera ® (atomoxetine HCl), Lamictal ®8/10 to 5/10 and patient (lamotrigine), and Abilify ® (aripiprazole)became more focused. in past. *2. 68 s/p Auto Accident with Cervical10-15 minutes after 30 mg y/o female Spondylosis, Disc Herniations,Muscle Cari-Derm, less muscle Spasms, and Anxiety, s/p steroid dosespasm and pain; more calm. pack with temporary relief Slight tinglingsensation in sternum. *3. 58 s/p Intracranial aneurysm rupture with 15Minutes after 30 mg Cari- y/o female Central Pain Syndrome, CentralDerm, BP reduced from Hypertension, and Neck Pain. On 200/120 to170/100; neck Tramadol, Klonopin ® (clonazepam), and head pain improvedTizanidine, and Soma ® (carisoprodol). 4. 51 Back Pain and PeripheralNeuropathic After Topical Cari-Derm, y/o female Pain pain in both areassignificantly improved from 8/10 to 4/10. 5. 49 R.N. with ChronicAnxiety Disorder, After 30 mg Cari-Derm, y/o female PTSD. anxietydiminished from 10/10 to 4/10. *6. 59 MS with Cognitive Dysfunction,After Cari-Derm, thinking y/o female Complex Partial Seizures,; Neck andmore clear, pain decreased Back Pain, Headache. On Vimpat ® by 40%.(lacosamide) and Cymbalta ® (duloxetine HCl). 7. 57 Dermatomyositis,Peripheral After30 mg Topical Cari- y/o female Neuropathic Pain, s/precent Hip Derm, both pain and anxiety Replacement, Anxiety Disorder. Ondiminished. Lyrica ® (pregabalin), Cymbalta ® (duloxetine HCl), Xanax ®(alprazolam). *8. 25 History of Chronic Dizziness and Light- TopicalCari-Derm reduced y/o female Headedness; had been on Antivert ®(meclizine) symptoms of dizziness and and Klonopin ® (clonazepam)without benefit. light-headedness. 9. 73 Long History of Seizures andRight Knee After topical 30 mg Cari- y/o female Pain. On Keppra ®(levitiracetam) for Derm, EEG and knee pain seizures and Plavix ®(clopidogrel bisulfate) improved. for TIA's. 10. 55 Chronic Seizures andEncephalopathy 10-15 minutes after 30 mg y/o male with Lethargy andDecreased Cari-Derm, was more alert, Spontaneity. On Keppra ®(levitiracetam), responsive, and talkative. Lamictal ® (lamotrigine),Trileptal ® (oxcarbazepine), and Remeron ® (mirtazapine). 11.23 Autismand Seizures with Poor Vision 15 minutes after 30 mg Cari- y/o male andFocus. Had been on Adderall ® Derm, improved focus and (amphetamine,dextroamphetamine mixed salts) vision. and Ritalin ® (methylphenidate)without benefit; increased agitation *12. 80 Cervical Spondylosis, s/psub-occipital After Topical Cari-Derm, y/o female craniotomy, and VPshunt for neck tension and pain hydrocephalus with neck pain. Ondiminished 50%. Zonisamide, Prozac ® (fluozetine HCl). 13. 67 Longhistory of Tinnitus/Ringing in Ears, After 30 mg Cari-Derm, y/o maleSinus Congestion, and Decreased sinus congestion relieved, Hearing LeftEar; using OTC anti- reduced tinnitus and histamines and decongestants.improved hearing. *,**14. 72 Seizures, Myasthenia Gravis, and AfterCari-Derm, neck range y/o female Torticollis with Neck Pain. On Keppra ®of motion improved with less (levitriacetam), tapered off Mestinon ®pain. Adding topical apomorphine (pyridostigmine). improved further. 15.29 Persistent Neuropathic Pain and Topical Cari-Derm resolved y/ofemale. Decreased Function after Dog Bite. Had pain and improvedfunction. been on Lyrica ® (pregabalin) and CBD topical cream. *16. 69Long History of Seizures and Tinnitus, After topical 30 mg Cari- y/oMale Right Ear Blockage Derm, ear popped open and tinnitus diminished,hearing improved. *17. 68 Chronic Sinus Congestion with Bilateral 10-15minutes after 30 mg y/o female Eustachian Tube Blockage, Left > Right.Cari-Derm, sinuses opened with less sensation of blockage. 18. 68 FailedBack Syndrome s/p 2 Back After application of 30 mg y/o male Operationswith Severe Cari-Derm to the back of Neuropathic pain in LowerExtremities: neck and lumbar spine, Left > Right, Insomnia. improvedneuropathic pain in legs. 19. 54 Fibromyalgia with neuropathic painright Neuropathic pain improved 70% y/o female elbow and arm for 1month. within 15 minutes of 30 mg Cari- Derm to elbow and back of neck**20. 86 3 year history of Parkinson's disease Improved tremors, morey/o female with isolation, cognitive blunting, and focused and talkativeafter tremors of upper extremities: L. > R. Cari-Derm; further improvedwith Apomorphine 5 mg. 21. 82 Parkinson's disease with rigidity, slowImproved mobility after 30 mg y/o male movement with gait disorder.Cari-Derm *22. 16 Long history of migraine headaches, 15 minutes afterCari-Derm y/o male sinus congestion, and anxiety. 3% sinuses opened upand anxiety decreased. **23. 73 s/p head injury, cervical and thoracicAfter topical 30 mg Cari- y/o male laminectomy with poor focus, Dem,improved focus and impulsivity and gait problems from spontaneity, andgait. After Parkinson's. additional 5 mg Apomorphine, furtherimprovement noted. 24. 46 Life long autism with schizoaffective After 30mg Cari-Derm to y/o male disorder, poor focus and chronic anxiety theback of neck, improved with excessive sweating. anxiety, focus withdiminished sweating, also noted on EEG. *25. 48 s/p concussion withvisual problems, After 30 mg Cari-Derm, y/o female headaches, muscletension and anxiety. improved vision, anxiety, focus with decreasedtension and spasm. *26. 58 Encephalopathy, neck pain and 30 mg Cari-Dermto back of y/o female headaches with cognitive dysfunction. neckimproved headache from 10 to 6/10, cognitive cloudiness improved. 27. 49Chronic anxiety with crying and Less stressed and better able y/o femaleemotional upset, PTSD. to deal with emotional issues after Cari-Dermtherapy. *28. 26 Seasonal allergies with sinus congestion 30 mgCari-Derm opened y/o female and daily headaches sinus congestion andrelieved headaches. *29. 58 s/p traumatic injury to right face with 30mg Cari-Derm to back of y/o male persistent neuralgic pain andheadaches. neck and right face decreased On Trileptal ®(oxycarbazepine), Gabapentin, neuropathic face pain and Diamox ®(acetazolamide), Cymbalta ® headache by additional 40%. (dulozetineHCl), and Misoprostol. *30. 78 s/p cervical fusion with daily headachesAfter topical 30 mg Cari- y/o female from temporal arteritis. Derm,improved neck range of motion, less pain. *31. 56 s/p numerous sinusoperations with After 30 mg Cari-Derm to y/o female atypical facialpain/Trigeminal the back of neck and 15 mg Neuralgia for 6 months onDilaudid ® to forehead, pain further (hydromorphone HCl), fentanylpatch. diminished over 80% from baseline. Now on 2x/day. *32. 47 longhistory of epilepsy and migraine Acute headache resolved y/o femaleheadaches, on Keppra ® (levitiractam), within 10-15 minutes of 30Gabapentin, Risperdone. mg at back of neck; also improved focus andanxiety. 33. 74 long history of Parkinson's disease, s/p Improvedakisthesias and y/o female recent renal stones extraction with pain fromkidney stones after persistent pain. 30 mg Cari-Derm. 34. 25 cerebralpalsy with spastic quadriparesis, 30 mg Cari-Derm improved y/o maleright > left; seizures with encephalopathy. spasticity and became morealert and interactive. *35. 24 chronic headaches and ADHD on 30 mgCari-Derm helped y/o female Vyvanse ® (lisdexamfetamine dimesylate),relieve headache but felt Diamox ® (acetazolamide), and topical CBDworked better. CBD cream which works well for migraines. 36. 64 s/pvertebral artery dissection with Cari-Derm to back of neck y/o maleposterior fossa stroke: right hemiparesis, improved visual symptomsnystagmus, opsillopsia, and dysarthria. and spasticity, speech. **37. 87long history of Parkinson's disease on Cari-Derm and Apomorphine y/omale Sinemet ® (carbidopa-levodopa) 6-7x/day combination to back of neckwith gait problems. improved gait and overall mobility. 38. 80 failedback syndrome, s/p lumbar Combination of 3% Cari- y/o male laminectomywith peripheral neuropathy Derm and 2 mg and narcotic dependency forpain Apomorphine improved back pain and gait, able to better controllegs. 39. 41 neonatal nuchal cord syndrome with after 3% Cari-Derm, lessy/o male chronic mood disorder, attentional anxious, focusing better,and issues, insomnia, and cognitive improved thought processes.processing. **40. 69 Parkinson's disease and tremors of hands: Cari-Dermand Apomorphine y/o female right > left, with tradive dyskinesias. Oncombination to back of neck Benadryl ® (diphenhydramine). improvedtremors. *,**41. 47 s/p auto accident with head injury, Improved neckrange of y/o male cervical and thoracic compression motion and less painafter fracture with neck spasm and pain. 3% Cari-Derm and 2 mgapomorphine combination to neck. 42. 68 lumbar radiculopathy andperipheral back pain and lower y/o male neuropathy extremity neuropathicpains improved after Cari-Derm 3%. *,**43. 58 long history of PTSD,fibromyalgia, and relief of headache by 60% y/o female tensionheadaches. with Cari-Derm and apomorphine combination to back of neck.44. 4 primary generalized epilepsy with Cari-Derm 3% to back of y/o maleagitation, attentional problems, and neck improved focus andimpulsivity. On Keppra ® (levitiracetam) impulsivity. and Depakote ®(divalproex sodium). *45. 68 fibromyalgia, seizures, chronic pain withtopical Cari-Derm 3% to y/o female numerous narcotics, metabolic back ofneck improved head encephalopathy, headaches and pain and photophobia;more photophobia. alert and responsive. 46. 64 history of posteriorfossa stroke and topical Cari-Derm 3% to y/o male vasculitis withheadaches and neck pain. back of neck improved headache and neck pain50% *47. 69 Trigeminal neuralgia with brain improved headache and necky/o female hyperintensities; cervical spondylosis tension with 3%Cari-Derm.. with tension headaches. *48. 70 long history of migrainesand cervical complete resolution of y/o female spondylosis with muscletension headache and neck tension headaches. from 6/10 to 0/10 in 10minutes after 3% Cari-Derm to neck. *49. 79 s/p cervical laminectomywith C5 15 minutes after Cari-Derm y/o male radiculopathy, muscletension headaches, to neck and back, resolution failed back with rightSI joint pain. of neck and back pain, headache. 50. 52 history ofseizures with encephalopathy, after 30 mg Cari-Derm, less y/o femalememory problems, focus issues, and anxiety. anxious and more alert andOn Lamictal ® (lamotrigine), Nameda ® focused. (memantine), andBystolic ® (nebivolol). 51. 80 20 yr. history of MS with weakness inCari-Derm 3% to back of y/o female lower extremities, in wheelchair. Onneck improved improved Avonex ® (interferon beta - 1a) 10 years.strength and movement in lower extremities. *52. 37 menstrual migrainessince age 12 with topical Cari-Derm 3% to y/o female transformed dailyheadaches from back of neck completely acetaminophen (Extra StrengthExedrin ® resolved head pain and (acetaminophen, aspirin, caffeine))photophobia; more alert and overuse. responsive. 53. 64 osteoporosiswith recent lifting back topical Cari-Derm 3% to y/o female injury lowerback improved back pain and mobility. 54. 48 history of seizures withrecent closed Topical 3% Cari-Derm to y/o female head injury with poorfocusing, cognitive back of neck improved EEG slowing, and peripheralneuropathic abnormalities and focus, symptoms. alertness. 55. 13 historyof back and joint pain, 3% Cari-Derm to neck and y/o male fibromyalgiawith hypotonia of muscles lower back alleviated back, knee, and anklejoint pains. **56. 69 history of MS with spasticity, gait 3% Cari-Dermand 5 mg y/o Female disturbance. apomorphine combination improvedspasticity and gait 57. 20 history of generalized, nocturnal, and 3%Cari-Derm to back of the y/o male complex partial seizures with anxietyneck improved focus and disorder; also has tremors of the hands.tremors. *58. 45 childhood history of migraines with Cari-Derm 3% toback of y/o female recent recurrence after auto accident and neckimproved headache and cervical sprain. neck muscle tension. 59. 79ischemic cerebrovascular disease with topical Cari-Derm 3% to y/o femaledementia and episodic memory loss, back of neck made her moreinattention. alert and responsive, and interactive. *60. 72 neck pain,anxiety, and peripheral topical Cari-Derm 3% to y/o female neuropathyneck improved anxiety; and reduced neck tension and pain. 61. 80 historyof MS, lumbar degenerative After topical Cari-Derm 3% y/o femaledisease, and bilateral knee pain, to the knee and back, left > right.improved mobility and pain. *62. 48 s/p 2 auto accidents with headinjuries; Topical Cari-Derm 3% y/o female headaches, visual blurring,and cognitive improved vision and focus, dysfunction with poor focus.resolved headache. EEG improved background. *63. 68 PTSD, cervicalspondylosis, with chronic topical Cari-Derm 3% y/o male tensionheadaches and migraines. improved neck ROM, muscle spasm and headaches.64. 51 s/p auto accident with head injury, Topical Cari-Derm 3% to y/ofemale cervical sprain with headaches, neck back of neck improved neckspasms, and poor concentration. tension and headache. 65. 58 longhistory of MS with lower extremity Cari-Derm 3% to back of y/o femalespasticity, s/p cervical fusion and lumbar neck and lower backlaminectomy. improved pain and spasticity to extent able to walk better.66. 49 PTSD, anxiety disorder. Topical Cari-Derm 3% to y/o female backof neck improved anxiety and resolved panic attack. 67. 7 Developmentaldelay, ADHD, anxiety topical Cari-Derm 3% to y/o Male with abnormal EEG.neck improved anxiety, improved focus; EEG background improved. *68. 56migraine headaches, eye twitching, and After topical Cari-Derm 3% y/ofemale anxiety. to back of neck, improved headache and anxiety. *69. 68lupus cerebritis, normal pressure Topical Cari-Derm 3% to y/o femalehydrocephalus, seizures, and headaches back of neck improved vision withdizziness and visual blurring. and focus, resolved headache. 70. 64bi-polar affective disorder, depression, topical Cari-Derm 3% to y/omale fatigue, and attentional problems. back of neck improved anxietyand focus. (*head pain, **combination therapy)

Example 6

Several combinations of caryophyllene and traditional compounds areformulated for topical therapy. These combinations are outlined belowusing either 2% or 3% caryophyllene, as set forth in Example 3.

The above 2% and 3% caryophyllene products are combined withtraditionally used pharmaceutical compounds to produce the following:

2-3% caryophyllene+5 mg melatonin for insomnia.

2-3% caryophyllene+Apomorphine 2 mg for Parkinson's disease, tremors,dystonia.

2-3% caryophyllene+10 mg phentermine for ADD/ADHD and Tourette's.

2-3% caryophyllene+25 mg milnacipran (Savella®) for anxiety & panicattacks, mood disorders.

2-3% caryophyllene+4-AP (4-amino pyridine) 5 mg for DPN & otherperipheral neuropathic conditions.

2-3% caryophyllene+4-AP 5 mg+apomorphine 2 mg for spasticity and spasms.

2-3% caryophyllene+sumatriptan+/−tizanidine 5 mg (optional activeingredient) for migraine, tension headache.

2-3% caryophyllene and 5 mg melatonin for insomnia.

2-3% caryophyllene and 2 mg apomorphine for spasticity, muscle spasm,tremor and Parkinson's disease.

2-3% caryophyllene and 5 mg 4-aminopyridine for stroke, MS,demyelinating disorders, and peripheral neuropathy.

2-3% caryophyllene and 25 mg sumatriptan for migraine attacks.

2-3% caryophyllene and 25 mg minacipran for seizures with anxiety andpanic attacks.

2-3% caryophyllene and 10 mg phentermine for ADD/ADHD.

The above dosage levels are examples only. one skilled in the art willappreciate that the dosage levels may be varied for the additionalagents, e.g., within at least the range of levels of these agentsapproved for other routes of administration. Further, the concentrationsof caryophyllene are based on an expected unit dose of topicalpharmaceutical formulation of about 1 gram. It is contemplated thathigher or lower concentrations can be used, with the end result beingthat the dose of caryophyllene contained in the unit dose would be inthe range from about 3 mg to about 200 mg, preferably from about 10 mgto about 40 mg, and in certain embodiments most preferably from about 15mg to about 30 mg.

CONCLUSION

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

The active agents may be incorporated into the topical formulations intherapeutically equivalent amounts. The actual dose of an active agent(relative potency) may be determined based on a comparative dose to atherapeutically effective dose of an active agent described herein.However, it is noted that the differences in oral doses may not directlycorrespond to the differences in doses that are therapeuticallyeffective via transdermal delivery of the serotonin agonist. Factorssuch as metabolism of the serotonin agonist, the ability of the drug topass through the skin, among others, may affect the amount of serotoninagonist necessary to provide a therapeutic effect. One skilled in theart would readily understand this and adjust for the same.

The hypotheses of the inventor provided throughout the specification arefor possible explanation purposes only, and are not meant to be limitingin any way.

1. A method of treating a CNS disease state or condition in human withcaryophyllene, comprising administering caryophyllene in atherapeutically effective amount to treat the CNS disease state orcondition, to the back of the neck region of a human patient to provideregional neuro-affective therapy to the human patient.
 2. The method ofclaim 1, wherein the back of the neck region comprises the area orregion extending from (behind) one ear to the other ear of the humanpatient and from the back of the head to below the hairline at the backof the neck of the human patient.
 3. The method of claim 1, wherein thecaryophyllene is administered such that it is absorbed in an area at orabove the skin where the afferent components of trigeminal nerve system,cervical sympathetic nerves, and vagus nerve are located.
 4. The methodof claim 1, wherein the caryophyllene is administered in a topicalpharmaceutical formulation in a unit dose containing a therapeuticallyeffective amount of the caryophyllene.
 5. The method of claim 1, whereinthe caryophyllene is administered in a topical pharmaceuticalformulation at the back of the neck at the hairline of the humanpatient.
 6. The method of claim 1, wherein the administration ofcaryophyllene is selected from the group consisting of topicaladministration, implantation, transdermal administration, or injection.7. The method of claim 1, wherein the caryophyllene is β-caryophyllene.8. The method of claim 1, wherein the caryophyllene is administered in aunit dose comprising from about 3 mg to about 50 mg caryophyllene. 9.The method of claim 1, wherein the caryophyllene is administered in aunit dose comprising from about 15 mg to about 30 mg caryophyllene. 10.The method of claim 4, wherein the unit dose comprises from about 10 mgto about 50 mg caryophyllene and the topical pharmaceutical formulationis in the form of a cream, gel, or foam.
 11. The method of claim 10,further comprising administering the topical pharmaceutical formulationfrom 1 to about 4 times daily.
 12. The method of claim 10, wherein thedisease state or condition is chronic, further comprising administeringa unit dose of the topical pharmaceutical formulation from 1 to about 4times per day.
 13. The method of claim 10, wherein the disease state orcondition is acute, further comprising administering a unit dose of thetopical pharmaceutical formulation from 1 to about 4 times per day untilpartial or complete relief is achieved.
 14. The method of claim 1,wherein the treatment further comprises administering to the back of theneck region together simultaneously or sequentially an additionaldrug(s) selected from the group consisting of an anti-epileptic, ananxiolytic, a neuroleptic, an anti-psychotic, an analgesic, ananti-inflammatory, an anti-Parkinson's disease/syndrome drug, a drug forthe treatment of dystonia, a drug for the treatment of spasticconditions, a drug for the treatment of benign essential/familialtremor, a drug for the treatment of tremor related to MS, a drug for thetreatment of chronic encephalopathies, a drug for the treatment ofcongenital CNS degeneration conditions/cerebral palsy, a drug for thetreatment of cerebellar degeneration syndromes, a drug for the treatmentof neuropathic and/or neurogenic pain, a drug for appetite suppression,a drug for neurodegenerative conditions, a drug for the treatment ofmultiple sclerosis, a drug for the treatment of insomnia, a drug for thetreatment of fatigue, a drug for the treatment of vertigo, nausea and/ordizziness, a drug for the treatment of writer's cramp and restless legsyndrome, other drugs which can beneficially be added to the treatmentin order to provide an additive or synergistic effect with respect totreating the patient's disease state or condition; and a combination ofany of the foregoing.
 15. The method of claim 1, wherein the treatmentfurther comprises administering to the back of the neck region togethersimultaneously or sequentially an additional drug(s) for a condition ordisease state selected from the group consisting of anxiety disorder;attention deficit disorder/poor focus; social isolation/autism-relatedsymptoms; muscle tension and spasm; seizures and associatedencephalopathy; headache; peripheral neuropathic pain and symptomsthereof; tinnitus/ringing in ears; arthritis related pain and decreasedrange of motion; dizziness and light-headedness.
 16. The method of claim1, wherein the patient is treated for a condition or disease stateselected from the group consisting of ADD; ADHD; Anxiety Disorder;Cervical Spondylosis; Disc Herniations; Muscle Spasms; Central PainSyndrome; Central Hypertension; acute pain; peripheral neuropathic pain;R.N. with Chronic Anxiety Disorder; PTSD; MS; seizures; headache;encephalopathy; lethargy; decreased spontaneity; gait disorder; autism;poor focus; tinnitus; myasthenia gravis; torticollis; fibromyalgia;Parkinson's disease; migraine; head or face injury; cervicallaminectomy; thoracic laminectomy; lumbar laminectomy; autism; cervicalfusion; cerebral palsy; spastic quadriparesis; vertebral arterydissection; posterior fossa stroke: hemiparesis; nystagmus; opsillopsia;dysarthria; failed back syndrome; neonatal nuchal cord syndrome; chronicmood disorder; insomnia; tardive dyskinesia; cervical and/or thoraciccompression fracture; lumbar radiculopathy; impulsivity; trigeminalneuralgia; cervical spondylosis; muscle tension headaches; ischemiccerebrovascular disease; eye twitching; lupus cerebritis; normalpressure hydrocephalus; bi-polar affective disorder; depression; andfatigue.
 17. A method of treating a CNS disease state or condition inhuman, comprising administering a unit dose comprising from about 3 mgto about 50 mg caryophyllene and a second therapeutically active drug totreat the CNS disease state or condition, to the back of the neck regionof a human patient to provide regional neuro-affective therapy to thehuman patient.
 18. The method of claim 16, wherein the back of the neckregion comprises the area or region extending from (behind) one ear tothe other ear of the human patient and from the back of the head tobelow the hairline at the back of the neck of the human patient.
 19. Themethod of claim 16, wherein the caryophyllene and the secondtherapeutically active drug are administered such that they are absorbedin an area at or above the skin where the afferent components oftrigeminal nerve system, cervical sympathetic nerves, and vagus nerveare located.
 20. The method of claim 16, wherein the secondtherapeutically active drug is selected from a triptan, melatonin,phentermine, an analgesic, 4-AP, apomorphine; a cannabinoid; an ergotalkaloid; a skeletal muscle relaxant; and mixtures of any of theforegoing.